Pharmacological Interventions for Smoking Cessation: an Overview and Network Meta-Analysis (Review)

Cochrane Database of Systematic Reviews

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review)

Cahill K, Stevens S, Perera R, Lancaster T

Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. www.cochranelibrary.com

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 3 OBJECTIVES ...... 5 METHODS ...... 5 RESULTS...... 8 Figure1...... 9 Figure2...... 16 Figure3...... 17 Figure4...... 18 DISCUSSION ...... 23 AUTHORS’CONCLUSIONS ...... 25 ACKNOWLEDGEMENTS ...... 26 REFERENCES ...... 26 ADDITIONALTABLES...... 31 APPENDICES ...... 43 WHAT’SNEW...... 49 CONTRIBUTIONSOFAUTHORS ...... 49 DECLARATIONSOFINTEREST ...... 49 SOURCESOFSUPPORT ...... 49 INDEXTERMS ...... 49

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) i Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Overview of Reviews] Pharmacological interventions for smoking cessation: an overview and network meta-analysis

Kate Cahill1, Sarah Stevens1, Rafael Perera1, Tim Lancaster1

1Nufﬁeld Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

Contact address: Kate Cahill, Nufﬁeld Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK. [email protected].

Editorial group: Cochrane Tobacco Addiction Group. Publication status and date: New, published in Issue 5, 2013.

Citation: Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2.

ABSTRACT

Background

Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline. Cytisine (a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of the former socialist economy countries. Other therapies, including nortriptyline, have also been tested for effectiveness.

Objectives

How do NRT, bupropion and varenicline compare with placebo and with each other in achieving long-term abstinence (six months or longer)?

How do the remaining treatments compare with placebo in achieving long-term abstinence?

How do the risks of adverse and serious adverse events (SAEs) compare between the treatments, and are there instances where the harms may outweigh the beneﬁts?

Methods

The overview is restricted to Cochrane reviews, all of which include randomised trials. Participants are usually adult smokers, but we exclude reviews of smoking cessation for pregnant women and in particular disease groups or speciﬁc settings. We cover nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate. Our outcome for beneﬁt is continuous or prolonged abstinence at least six months from the start of treatment. Our outcome for harms is the incidence of serious adverse events associated with each of the treatments.

We searched the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with ’smoking’ in the title, abstract or keyword ﬁelds. The last search was conducted in November 2012. We assessed methodological quality using a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we conducted network meta-analyses, comparing each with the others and with placebo for beneﬁt, and varenicline and bupropion for risks of serious adverse events.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 1 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Main results We identified 12 treatment-specific reviews. The analyses covered 267 studies, involving 101,804 participants. Both NRT and bupropion were superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47). Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than ’other’ NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT also outperformed single formulations. The four categories of NRT performed similarly against each other, apart from ’other’ NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Across the 82 included and excluded bupropion trials, our estimate of six seizures in the bupropion arms versus none in the placebo arms was lower than the expected rate (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention. Nicobrevin’s UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments. Authors’ conclusions NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting. Combination NRT and varenicline are equally effective as quitting aids. Nortriptyline also improves the chances of quitting. On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use. Further research is warranted into the safety of varenicline and into cytisine’s potential as an effective and affordable treatment, but not into the efficacy and safety of NRT.

PLAIN LANGUAGE SUMMARY Medications to help people to stop smoking: an overview of reviews Background Smoking is a main cause of early death throughout the world. There are a number of medications which can help people to quit smoking. Three of these, nicotine replacement therapy (NRT), bupropion and varenicline, are licensed for this purpose in the USA and Europe. Cytisine (similar to varenicline) is licensed for use in Russia and Eastern Europe. We reviewed studies of these and other treatments, including nortriptyline, to compare their beneﬁts and risks. Methods We found 12 Cochrane reviews of different treatments. The treatments include nicotine replacement therapy (NRT); antidepressants (bupropion and nortriptyline); nicotine receptor partial agonists (varenicline and cytisine); anxiolytics; selective type 1 cannabinoid receptor antagonists (rimonabant); clonidine; lobeline; dianicline; mecamylamine; Nicobrevin; opioid antagonists; nicotine vaccines; and silver acetate. The reviews were conducted between 2008 and 2012, and analysed 267 trials, covering more than 101,000 smokers. All the reviews used randomised controlled trials, and compared the active treatment with a placebo, and sometimes with other

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 2 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. treatments. The outcomes were measured at least six months from the start of treatment, and the results were usually checked by testing breath, blood or urine. We also assessed the risk of harms from each treatment. We then compared NRT, bupropion and varenicline with each other, using a network meta-analysis.

Results

NRT and bupropion helped about 80% more people to quit than placebo; this means that for every 10 people who quit with placebo about 18 could be expected to quit with NRT or with bupropion. Varenicline more than doubled the chances of quitting compared with placebo, so that for every 10 who quit with placebo about 28 could be expected to quit with varenicline.

Varenicline helped about 50% more people to quit than nicotine patch and ’other’ NRT (tablets, sprays, lozenges and inhalers), and about 70% more people than nicotine gum. So for every 10 people who quit with NRT patch or with ’other’ NRT, about 15 could be expected to quit with varenicline, and for every 10 who quit with NRT gum about 17 could be expected to quit with varenicline. Combining two type of NRT was as effective as using varenicline, and helped more people to quit than single types of NRT. There was little to choose between different types of NRT, apart from ’other’ NRT, which helped slightly more people than nicotine gum; for every 10 people who quit with NRT gum, about 12 could be expected to quit with ’other’ NRT.

NRT combined with nortriptyline or with bupropion was not more effective than NRT alone.

Both cytisine and nortriptyline compared with placebo improved the chances of quitting, with minimal risk of harms.

Bupropion carries a known risk of seizures (about 1 per 1000 users), but we found fewer than expected in the included and excluded trials, at about 1 in 1500. Although there may be a marginal increase in the likelihood of any serious adverse event while taking bupropion, we did not ﬁnd increased risks of neuropsychiatric or heart and circulatory problems in the bupropion studies. The evidence for the safety of varenicline is still under investigation; we found no evidence from the trials that it is linked to an increase in neuropsychiatric problems, or with increased heart and circulatory problems.

Clonidine helped people to quit, but caused side effects. It is not clear whether or not mecamylamine used with NRT helps people to quit. Other treatments did not seem to help. So far, nicotine vaccines are not licensed for use anywhere in the world. Nicobrevin is no longer available in the UK, and rimonabant, taranabant and dianicline have all been withdrawn from the market.

Conclusions

NRT, bupropion and varenicline all improve the chances of quitting, with a low risk of harms.

Combination use of NRT is as effective as varenicline, and more effective than single types of NRT.

Cytisine has potential as a safe, effective and affordable treatment.

Nortriptyline improves the chances of quitting, with little evidence of harmful events.

We need continued monitoring of the safety of varenicline.

More research into NRT versus placebo is unlikely to change our understanding of the treatment.

BACKGROUND 2006). There are more than 435,000 smoking-related deaths annually in the United States (Fiore 2008), and 82,900 in England Smoking remains the leading preventable cause of illness and pre- (NHS 2008). Morbidity associated with tobacco use includes a mature death worldwide, accounting for 20% of deaths in men broad range of cancers, respiratory and cardiovascular diseases. It over 30 years of age, and 5% in women (Disease Control Priorities

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 3 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. has been estimated that for every death caused by smoking, ap- treatment was first developed in the 1970s, and is widely avail- proximately 20 smokers are suffering from a smoking-related ill- able on prescription, or as an over-the-counter purchase in many ness (MMWR 2003). countries. However, the World Health Organization currently estimates that at least 38 countries do not yet support any provision of NRT (WHO 2009). In China and Russia, the prevalence of smoking among adult men 2. Bupropion: This was developed as a non-tricyclic antidepressant, exceeds 60% (Tobacco Atlas 2010). Currently in the USA and the and is sometimes preferred by smokers who do not wish to use a UK, around 21% of adults continue to smoke (MMWR 2007; nicotine-based treatment, or who have already failed to quit using Fiore 2008; GLS 2009). In 2007, 70% of American smokers and NRT. The usual dose for smoking cessation is 150 mg once a day 74% of British smokers reported that they wanted to quit, with for three days increasing to 150 mg twice a day, continued for 7 most citing health and financial reasons (Fiore 2008; NHS 2008). to 12 weeks. The quit attempt is generally initiated a week after In a survey of more than 5,000 adults in England in 2006, about starting pharmacotherapy. half of those smoking had made at least one quit attempt in the past 3. Nortriptyline: This is a tricyclic antidepressant, and is sometimes year, yielding an estimated permanent cessation rate of between 2 prescribed when first-line treatments have been unsuccessful. It is and 3% annually (West 2006). licensed as a smoking cessation aid in New Zealand. The recommended regimen is a period of titration (10 - 28 days) before the quit attempt, and a 12-week therapeutic dose of 75 to 100 mg daily. Description of the condition These medications are available only via prescription. 4. Varenicline: This is a selective nicotinic receptor partial agonist, Tobacco products contain nicotine, a substance now acknowl- licensed as a prescription-only treatment for smoking cessation in edged to be as addictive as heroin or cocaine (SCOTH 1998; RCP the USA in 2006, and in Europe in 2006/2007. The standard 2000). Nicotine triggers the release of dopamine and other neuro- regimen is 1mg twice a day for 12 weeks, with the first week titrated transmitters in the brain, which reinforce the smoker’s dependence to reduce side effects, and quit date set for the second week. on tobacco. With long-term habituation, smoking may become a 5. Cystisine: This is pharmacologically similar to varenicline. Al- self-medicating behaviour, which reduces negative affect and mod- though it has been used for almost 50 years as a cessation aid, it ulates withdrawal symptoms, over and above its positive reinforce- is currently licensed only in Russia and in some former socialist ment properties (Benowitz 2008). Smokers with life-threatening economy countries, including Poland and Bulgaria. The standard illnesses that may in part be attributable to their use of tobacco regimen is a 25-day course, gradually reducing from six 1.5 mg still have great difficulty in achieving permanent abstinence, with tablets a day to two tablets a day by the end of the treatment pe- as many as 70% of those surviving a heart attack resuming smok- riod, with a quit date set for day five. ing within a year (40% while still in hospital), and about 50% of Other medications which we cover in this overview include: lung cancer patients returning to smoking after surgery (Stapleton • Antidepressants, including tricyclics, monoamine oxidase 1998). inhibitors, selective serotonin reuptake inhibitors, atypical antidepressants, and extracts of Hypericum perforatum (St John’s Wort) Description of the interventions • Anxiolytics, including buspirone, diazepam, doxepin, meprobamate, ondansetron, and the beta-blockers metoprolol, NRT, bupropion and varenicline are widely available on prescrip- oxprenolol and propanolol tion and in the case of NRT as an over-the-counter medication. • Selective cannabinoid type 1 receptor antagonists, They are licensed as first-line treatments for use as smoking cessa- including rimonabant and taranabant tion aids in the USA and the European Union, and are widely rec- • Clonidine ommended in many national guidelines. We have therefore con- • Lobeline, dianicline centrated on these three treatments in this overview. However, we • Mecamylamine also review the efficacy and safety of cytisine, a selective nicotinic • Nicobrevin (a proprietary brand mixture of quinine, receptor partial agonist of a similar type to varenicline, and the camphor, menthol and eucalyptus oil) antidepressant nortriptyline. • Nicotine vaccines 1. Nicotine replacement therapy (NRT). This aims to reduce mo- • Opioid antagonists, including naltrexone, naloxone and tivation to smoke and the physiological and psychological with- buprenorphine drawal symptoms often experienced during a quit attempt. It is • Silver acetate available as patches in various dosages (absorbed slowly through the skin), and as chewing gum, lozenges, sublingual tablets, sprays and inhalers (absorbed through the oral or nasal mucosa). The

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 4 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. How the intervention might work 3. Which of the other available pharmacological treatments might help smokers to quit? Different treatments incorporate different mechanisms, but the underpinning principles are: 4. Are there limitations in the current evidence base which may (i) to mitigate the craving and withdrawal symptoms often asso- compromise the precision or stability of any conclusions drawn by ciated with a quit attempt, and/or this overview? If so, what are the implications for future research? (ii) to reduce the reward derived from smoking by indirectly dis- rupting dopamine release or by desensitising receptors, and/or (iii) to deliver some positive reinforcement other than from a cigarette. METHODS It should be noted that the precise mechanisms for some therapies are still under investigation. The major mechanisms of action, singly or in combination, are believed to be: Criteria for considering reviews for inclusion • to block nicotine or blunt the effects of nicotine on its Types of studies receptors or receptors in pharmacological pathways affected by In accordance with the standard criteria for Cochrane reviews of nicotine; these include bupropion, vaccines, mecamylamine, the pharmacological treatments for smoking cessation, we have re- nicotine receptor partial agonists (varenicline, cytisine, stricted the included studies in this overview to randomised con- dianicline), selective type 1 cannabinoid receptor antagonists trolled trials for the estimation of efficacy. For an assessment of (rimonabant, taranabant), and the opioid antagonists; * harmful effects we have also included post-marketing surveillance • to relieve withdrawal: these include nicotine replacement data where these are available and appropriate. therapies, lobeline, varenicline, Nicobrevin; Types of participants • to substitute for nicotine’s effects: these include anxiolytics, We include all participants covered by the pharmacotherapy-based antidepressants, clonidine, bupropion; (’primary’) reviews included in this overview. These are usually • aversive therapy: silver nitrate; adult smokers, of either gender, and of any nationality and ethnic- • sensory replacement: Nicobrevin. ity. We have not included all the data from those reviews which focus on particular populations of smokers, e.g. adults with men- tal health problems (Tsoi 2010; van der Meer 2009), smokeless Why it is important to do this overview tobacco users (Ebbert 2011), or pregnant women (Lumley 2009), There is currently a range of pharmacological treatments to help as such reviews cover a range of interventions beyond the pharma- smokers who wish to quit, and a considerable body of research cotherapies which are the subject of this overview. However, trials which tests both their efficacy and their safety. The aim of this of pharmacological interventions which target specific groups of review is to provide relevant information to tobacco users, clini- smokers, settings, intervention delivery and cessation techniques cians and policy makers, and to attempt to balance the potential are included within the relevant sections of this overview, classified benefits and harms associated with the treatments. by the type of intervention. Types of interventions Interventions include nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor par- OBJECTIVES tial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lo- To conduct an overview of Cochrane reviews which assess the beline, dianicline, mecamylamine, Nicobrevin, opioid antago- efficacy and safety of pharmacological interventions designed to nists, nicotine vaccines, and silver acetate. These interventions may support smoking cessation attempts. be delivered as monotherapies or in combination. As part of this overview, we address the following issues: We assess the impact of variations in the formulations (e.g. different types of NRT), and single versus combination treatments. 1. How do nicotine replacement therapy, bupropion and vareni- The comparison conditions include placebo, other pharmacolog- cline compare with each other for efficacy, defined in this overview ical treatments or combinations of treatments, and usual or stan- as the achievement of long-term abstinence (six months or longer)? dard care. This question is explored using direct and indirect comparisons Types of outcomes where appropriate. The primary beneficial outcome for this overview is sustained 2. How do the risks of adverse and serious adverse events compare smoking cessation, i.e. for six months or longer. The preferred out- between the treatments, and are there instances where the harms come is biochemically validated continuous or prolonged absti- significantly outweigh the benefits? nence at the longest reported time point, and including all partic-

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 5 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ipants randomised in their original groups (an intention-to-treat extracted. Any persistent disagreement would have been referred analysis). to the fourth author (TL) for discussion and resolution. Secondary beneficial outcomes include: • reduction of withdrawal symptoms • reduction of craving Assessment of methodological quality of included reviews Although some clinical trials include smoking reduction as one of their target outcomes, the primary outcome of interest for this We used the AMSTAR measurement tool (adapted from Shea overview is limited to abstinence from smoking. 2007; Evans 2009) to assess the quality of the included reviews. The primary harmful outcome is any serious or life-threatening This modified instrument comprises the following 11 items: adverse event which may, in the trialists’ opinion, be attributable to 1. Was an ’a priori’ design provided?. the pharmacological treatment. These may include psychological 2. Was there duplicate study selection and data extraction? disorders, such as depression, anxiety, suicidal ideation or suicidal 3. Was a comprehensive literature search performed? behaviour, and neurological events such as seizures. 4. Were published and unpublished studies eligible, irrespective Secondary harmful outcomes will vary between treatments, but of language of publication? may include: 5. Was a list of studies (included and excluded) provided? • psychiatric disorders 6. Were the characteristics of the included studies provided? • gastrointestinal disorders 7. Was the scientific quality of the included studies assessed and • cardiovascular problems documented? • insomnia and other sleep disorders 8. Was the scientific quality of the included studies used appro- • skin disorders priately in formulating conclusions? • allergic or hypersensitive reactions 9. Were the methods used to combine the findings of studies • drop-outs due to adverse events appropriate? 10. Was the likelihood of publication bias assessed? 11. Was the conflict of interest stated? Search methods for identification of reviews Each criterion is rated as ’Yes’ (definitely done), ’No’ (definitely not done), ’Can’t answer’ (status unclear) or ’Not applicable’. A We searched the Cochrane Database of Systematic Reviews ’Yes’ rating is taken to indicate adequate quality. Criteria rated as (CDSR) in The Cochrane Library, for any reviews with “smoking” ’Not applicable’ (e.g. legitimacy of methods for combining studies in the title, abstract or keyword fields. The search was conducted where included studies were absent or could not be combined) in November 2012. We then identified reviews of pharmacologi- are not counted against the review, but are removed from the cal treatments for smoking cessation, for possible inclusion in this denominator with appropriate adjustment to the ranking (Shea overview. Since Cochrane reviews strive for methodological rigour 2011). and are regularly updated, we have not sought non-Cochrane re- We have ranked the included reviews as being of high quality views for inclusion within this overview. (scoring 8-11), of medium quality (scoring 4-7), or of low quality (scoring 0-3). We have not excluded reviews on the basis of AMSTAR rankings, but have conducted sensitivity analyses where Data collection and analysis applicable to explore the consequences of synthesising reviews of differing quality. We have evaluated the overall quality of the evidence for each outcome using the GRADE system (Atkins 2004). This approach Selection of reviews identifies four elements which influence the quality of the evi- Two authors (KC and RP) independently assessed all potentially dence: these are study design, study quality, consistency (between eligible reviews identified by the search strategy. estimates of effect across studies) and directness (i.e. applicability of participants, interventions and outcomes to the clinical question under consideration). Assessing and combining these com- Data extraction and management ponents determine the initial grade of the evidence as: We extracted data from each included review. The data extraction • High: Further research is very unlikely to change our form summarises key information from each review, including de- confidence in the estimate of effect tails of the participants, the interventions, the comparisons and • Moderate: Further research is likely to have an important the outcomes. Outcomes wherever possible include both benefi- impact on our confidence in the estimate of effect and may cial and harmful effects of the treatments. One author (KC) ex- change the estimate. tracted the data, and a second author (RP) verified the information • Low: Further research is very likely to have an important

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 6 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. impact on our confidence in the estimate of effect and is likely to comparisons to estimate indirect pairwise comparisons not previ- change the estimate. ously tested. For example, in a pairwise meta-analysis, to compare • Very low: Any estimate of effect is very uncertain. the effect of treatment A with treatment B, only trials comparing A and B directly in the same trial are included in the analysis. The initial assessment is determined by the study design: However, in a network meta-analysis, it is also possible to use in- randomised trial = high formation from trials comparing A with C and B with C, where Observational study = low C is a common comparator treatment. To do this, we assume that Any other evidence = very low. the effect of A compared to B is given by the effect of A compared to C plus the effect of C compared to B. The grade is then decreased if: We estimated log-odds ratios from a random-effects homogeneous • Serious (-1) or very serious (-2) limitation to study quality variance consistency model using MCMC simulation (Lu 2004; • Important inconsistency (-1) Lu 2006: van Valkenhoef 2012a) and non-informative prior prob- • Some (-1) or major (-2) uncertainty about directness abilities. For each of the three models 100,000 burn-in iterations • Imprecise or sparse data (-1) were performed followed by 100,000 updates, across four chains. • High probability of reporting bias (-1) For the estimation we used a thinning interval of 10. We assessed The grade is increased if: convergence using the Brooks-Gelman-Rubin diagnostic tool and • Strong evidence of association - significant risk ratio of >2 visual inspection of diagnostic plots (Brooks 1998). Although the (<0.5) based on consistent evidence from two or more source reviews report their findings as fixed-effect risk ratios, we observational studies, with no plausible confounders (+1) have generated odds ratios for the network meta-analyses, in ac- • Very strong evidence of association - significant risk ratio of cordance with the properties of the Bayesian model, i.e. relative >5 (<0.2) based on direct evidence with no major threats to effects between treatments are assumed additive (consistent) and validity (+2) approximately normally distributed, on the log-odds scale. • Some (-1) or major (-2) uncertainty about directness To determine whether the assumption of consistency was valid, • Evidence of a dose-response gradient (+1) we compared the consistency model results with those from an in- • All plausible confounders would have reduced the effect consistency model. The inconsistency model relaxes the assump- (+2) tion that the relative effects are additive on the log-odds scale. We also compared the deviance information criterion (DIC) statistic from both models. A difference of 3 or more between the two Data synthesis DIC values is thought to be meaningful and an indication that the consistency assumption may not be met (Spiegelhalter 2002). We To assess the efficacy of the target treatments, we have as far as performed consistency and inconsistency model simulations using possible conducted this overview at review level, and have not re- R (2.15.1; Team 2012) and the GeMTC package (van Valkenhoef analysed the included studies within the candidate reviews, but 2012b). DIC calculations were made using GeMTC 0.14 (van have used the existing point estimates and pooled analyses. We Valkenhoef 2012a) to generate JAGS code and the R/JAGS in- present direct comparisons wherever possible, but where head-to- terface package RJAGS (Plummer 2003; Plummer 2012; Team head comparisons of adequate quality were not available (e.g. NRT 2012). We also include distribution of probabilities ranking plots versus varenicline) we have undertaken indirect comparisons. for the efficacy of smoking cessation treatments. Where the source reviews include meta-analyses, we conducted In our review, the large number of studies included for each one comparisons of the pooled estimates of efficacy for each treatment of the head-to-head comparisons make the choice of priors less versus placebo, taking account of the definition of abstinence (con- crucial in determining the final estimates. As a reflection of this, tinuous, prolonged, point prevalence) and the length of follow-up there is good agreement between the point estimates and the 95% (six or twelve months). Where the source reviews do not include confidence interval and 95% credibility interval from the direct meta-analyses [lobeline, mecamylamine, Nicobrevin] we incorpo- and indirect comparisons. These are presented in Appendix 1, and rate brief narrative assessments. the rationale for the choice of priors in Appendix 2. For NRT, bupropion and varenicline, we have conducted two sep- To assess serious adverse events (SAEs), we have revisited where arate network meta-analyses using study level data and a Bayesian possible the individual trials and conducted additional binary hierarchical model approach. The first analysis compares the ef- (non-network) meta-analyses. The data were retrieved from a mix- ficacy of all three treatments with that of placebo and the sec- ture of published trial reports and from study-based web synopses ond analysis also assessed efficacy but with NRT split by type released by Pfizer Inc (manufacturers of varenicline). NRT has not (patch, gum, combination or ’other’ (inhalers, sprays, tablets and been included in these analyses, as we found little or no informa- lozenges)). tion about SAEs in the trial reports. Network meta-analyses differ from standard pairwise meta-anal- Although we intend to maintain this overview with timely updates, yses primarily because they use information across all available

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 7 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. in accordance with Cochrane policy, these will not necessarily other 12 reviews included one or more comparisons of pharma- be triggered by updates to the included reviews. Our decision cological products among the range of interventions that they to update the overview will be influenced by the likelihood that tested (see Figure 1, PRISMA diagram). Of the latter group 11 updates to the source reviews may substantively modify the key covered NRT, six covered bupropion, two covered varenicline, findings of this overview. and one covered naltrexone. They focused on candidate groups of smokers (Adolescent cessation 2006; COPD patients 2001; Hospital patients 2012; Pre-operative patients 2010; Pregnancy 2009; Schizophrenia 2010), on settings (Internet 2010; Workplace 2008), on healthcare providers (Pharmacists 2004), and on ces- RESULTS sation techniques (Reduction vs abrupt 2010; Relapse prevention 2009; Weight gain prevention 2009). Apart from two of the bupro- We restricted our searching to the Cochrane Database of System- pion trials (Levine 2010; Planer 2011) which will be considered atic Reviews (CDSR), and identified 60 full reviews with ’smok- for inclusion in the next update of Antidepressants 2007, we did ing cessation’ in the title, abstract or keywords. Thirty-six of these not find additional data to supplement that already covered in the were discarded as not including pharmacotherapies among their treatment-based reviews. interventions. Of the remaining 24, 12 reviews had at least one pharmacotherapy as their main or only intervention, while the The most recent search was conducted in November 2012.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 8 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 1. Study ﬂow diagram.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 9 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Description of included reviews tine spray, four of nicotine inhaler, one of oral spray, one providing This overview covers 12 Cochrane reviews, which investigate 26 patch plus inhaler and one providing patch plus lozenge. pharmacotherapies. The most prominent of these are nicotine Participants replacement therapy (NRT 2012), bupropion (Antidepressants Adult smokers, motivated to quit, apart from one trial which re- 2007) and varenicline (Nicotine receptor partial agonists 2012), cruited adolescents. Most trials recruited men and women, but all of which are licensed as treatments for smoking cessation in one recruited only men in a workplace setting. Four trials recruited high-income countries The key features of all the included reviews only women, and four more recruited pregnant women. Two trials are displayed in Table 1. recruited African-American smokers. All of the reviews used a similar methodological approach, and the Interventions and comparisons same primary outcome of abstinence from smoking for at least six As well as different types of NRT (gum, patches, lozenges or tablets, months. We used the most rigorous definition of abstinence avail- sprays and inhalers) versus placebo, the trials covered different able, i.e. preferring prolonged, sustained or continuous abstinence doses of NRT,comparing combination use of NRT to a single type, over point prevalence (Hughes 2003), and favouring biochemi- comparing NRT to bupropion and combinations of the two, and cally confirmed findings (exhaled carbon monoxide, cotinine in comparing the use of NRT pre-quit date as opposed to post-quit plasma, urine or saliva, or plasma thiocyanate) over self report date only. Some analyses also stratified on the level of behavioural (SRNT 2002). Study participants who dropped out during the support provided, i.e. low intensity (<30 minutes) or high intensity trial or who were lost to follow-up were assumed to be continuing (>30 minutes or multi-session counselling). smokers, and were included in the meta-analysis denominator on Most trials comparing nicotine gum to control provided the 2 mg an intention-to-treat basis. Opioid antagonists 2009 also included dose. A few provided 4 mg gum to more highly addicted smokers, a group of short-term trials (less than six months follow-up) which and two used only the 4 mg dose. Five trials included a comparison assessed withdrawal symptoms, attenuating the reinforcing value of 2 mg and 4 mg doses. The treatment period was typically two of smoking, and reducing ad libitum smoking. A second primary to three months, but ranged from three weeks to 12 months. outcome in all reviews was the incidence and severity of adverse For the patch trials, the usual maximum daily dose was 15 mg and serious adverse events (SAEs). for a 16-hour patch, or 21 mg for a 24-hour patch. Forty-two The sum total of participants across 267 studies within the in- studies used a 24-hour formulation, 11 a 16-hour product, and cluded reviews is 101,804. However, this computation may in- one a 52.5 mg/24 hour patch. The minimum duration of therapy clude a measure of double-counting, as some placebo participants ranged from three weeks to three months, with a tapering period, were compared, but not pooled, across multiple arms of several if required, in 38 of the trials. studies. Counts by treatment, together with estimates of efficacy Six studies tested nicotine sublingual tablets or lozenges, four within the source reviews (risk ratio and 95% confidence interval) tested intranasal nicotine spray, one tested oral nicotine spray and are given in Appendix 3. four tested nicotine inhaler. Nine trials compared combinations We briefly describe the individual reviews included in this of two forms of nicotine therapy to one form only. overview. Seven trials tested the use of NRT compared to placebo or control prior to quit date, with all study arms receiving NRT from the quit 1. NRT 2012 date onwards. Three of the trials also included a mecamylamine arm. The aim of nicotine replacement therapy (NRT) is to temporar- Five trials directly compared nicotine to bupropion, with three of ily replace some of the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms, thus easing the them also comparing nicotine-plus-bupropion to nicotine alone. Outcomes transition from cigarette smoking to complete abstinence. The au- One hundred and five trials (70%) reported some measure of sus- thors searched the Cochrane Central Register of Controlled Trials tained abstinence, which included continuous abstinence with not and online registers of ongoing and completed studies (e.g. UK even a slip since quit day, repeated point prevalence abstinence Clinical Trials; US Clinical Trials; WHO trials registry platform). (with or without biochemical validation) at multiple follow-ups, or The most recent search for this review was July 2012. The authors identified 150 included trials, with 117 (more than 51,000 self-reported abstinence for a prolonged period. Forty trials (27%) reported only point prevalence abstinence at the longest follow- participants across 122 comparisons) contributing to the primary up. In five studies it was unclear exactly how abstinence was de- effect measure comparing any type of NRT to a placebo or non- fined. The definition of abstinence in four studies permitted the NRT control group. These represented 55 trials of nicotine gum, smoking of two to three cigarettes a week. 43 of transdermal nicotine patch, six of an oral nicotine tablet or Most studies reported follow-up at least 12 months from start lozenge, five offering a choice of products, four of intranasal nico-

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 10 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. of treatment, but 33 reported only to six months. Four trials in One trial compared venlafaxine to placebo. pregnant women reported follow-up in relation to gestation and Outcomes delivery date. Twenty-two of the bupropion versus placebo studies followed participants for at least 12 months from the start of treatment or the target quit day. Eighteen studies (37%) had only six months fol- 2. Antidepressants 2007 low up. The majority of studies reported an outcome of sustained abstinence. In 12 (24%) only point prevalence rates were given, This review covers a group of medications, including nortripty- or the definition of abstinence was unclear. In all but one of the line; doxepin; fluoxetine; imipramine; moclobemide; paroxetine; bupropion studies and all but one of the nortriptyline studies bio- selegiline; sertraline, tryptophan, venlafaxine and St. John’s wort, chemical verification was used for most self-reported quitters at but we focus here on bupropion, a widely-used smoking cessation some assessment points. therapy, and also on nortriptyline. Bupropion was first approved as a treatment for depression in 1985, and was subsequently licensed as an aid for smoking cessation in 1997. It has both dopamin- ergic and adrenergic actions, and appears to be an antagonist at 3. Nicotine receptor partial agonists 2012 the nicotinic acetylcholinergic receptor. It may work by blocking Nicotine receptor partial agonists, including varenicline, cytisine nicotine effects, relieving withdrawal or reducing depressed mood. and dianicline, may help people to stop smoking by a combina- The authors searched the Cochrane Central Register of Controlled tion of maintaining moderate levels of dopamine to counteract Trials, as well as online registers of ongoing and completed clinical withdrawal symptoms (acting as an agonist) and reducing smok- trials. The searches for the current review were conducted in June ing satisfaction (acting as an antagonist). The authors searched the 2009. Tobacco Addiction Group’s specialised register, in the Cochrane There were 49 included trials of bupropion, covering more than Central Register of Controlled Trials, as well as online registers of 14,000 participants; four of the study reports were based on con- ongoing and completed clinical trials. The searches for the current ference abstracts or pharmaceutical company data. There were also review were conducted in December 2011. The authors identified nine trials of nortriptyline, six of selective serotonin reuptake in- 24 included studies, i.e. 20 for varenicline, three for cytisine and hibitors (SSRIs), four of monoamine oxidase inhibitors (MAOIs), one for dianicline. Fourteen of the varenicline trials were included and one of venlafaxine. in the main meta-analysis, covering more than 6000 participants. Participants Two of the varenicline trials were based on pre-publication data, Most trials recruited adult current smokers, with one trial con- acquired from the authors or from results posted on the online fined to men only. For the bupropion trials, special populations clinical trials registers. recruited include smokers with the following conditions: chronic Participants obstructive pulmonary disease (three trials); schizophrenia (five Adult smokers, motivated to quit. Apart from one trial, all were trials); post traumatic stress disorder (one trial); alcoholism (one multi-centre; while most were set wholly or partly in the USA, trial); and cardiovascular disease (three trials). Other populations three were conducted in Asian populations, and one across Latin included adolescents (two trials) and one trial each in smokers America, Africa and the Middle East. Five trials studied specific pa- awaiting surgery, hospital staff, healthcare workers, African-Amer- tient populations: schizophrenia or schizoaffective disorders; car- icans, and Maori. Two studies recruited smokers who had previ- diovascular diseases; acute smoking-related illnesses; hospital in- ously failed to quit smoking using bupropion, and one included patients; chronic obstructive pulmonary disease. The three cyti- smokers who had recently failed to quit using NRT. sine trials were set in the former German Democratic Republic, Interventions and comparisons in Kyrgyzstan and in Poland. The dianicline trial was set in six Thirty-six of the trials used bupropion as the only intervention European countries. versus placebo, covering more than 11,000 participants. Three Interventions and comparisons trials compared it as the sole intervention to nicotine patch, and Fifteen randomised controlled trials of varenicline compared it three more compared it to varenicline. Three of the bupropion/ to placebo. Three of these also included a direct comparison to placebo trials included a nortriptyline arm. Six trials compared bupropion. One trial compared varenicline plus counselling to bupropion combined with NRT to NRTalone. counselling alone, and another tested varenicline against placebo, Six nortriptyline trials compared it to placebo, and four combined as maintenance therapy for those who had already quit with nortriptyline with NRT versus NRT alone. varenicline. Two open-label trials compared varenicline to nico- Six trials tested SSRIs: these were two trials of fluoxetine versus tine patches. The standard regimen was 1.0 mg twice a day for placebo, two of fluoxetine plus NRT versus placebo plus NRT, 12 weeks, but three trials included lower dosage arms, versus stan- and one each of paroxetine and sertraline. dard dosage and placebo regimens, and two trials evaluated flexi- Four trials tested MAOIs, i.e. one trial of moclobemide versus ble dosing schedules or flexible quit dates. All trials delivered brief placebo, and three of selegiline versus placebo. behavioural support (10 minutes or less) to all participants during

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 11 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. treatment and follow-up phases. information on abstinence criteria and did not validate, and one Three trials compared cytisine to placebo, and one compared di- measured reduction rather than complete abstinence. None of the anicline to placebo. trials gave adequate details of randomisation procedures, but sim- Outcomes ply described their trial as “randomised”; one reported assigning All but three of the included studies reported prolonged, sustained to balance sex ratio and cotinine level, i.e. amount smoked, and or continuous abstinence. They all measured abstinence at 24 to another stratified by social class but gave no further information. 26 weeks, and again at 52 weeks in all bar eight. All the varenicline trial outcomes were biochemically verified by expired carbon monoxide, apart from two which relied upon self-report where 5. Clonidine 2008 biochemically verified data were not available, and one which ver- Clonidine was originally used to lower blood pressure. It acts on the ified outcomes at 12 but not at 24 weeks. central nervous system and may reduce withdrawal symptoms in All three cytisine trials assessed abstinence at six months, and con- various addictive behaviours, including tobacco use. The authors ducted final follow-up at two years. The dianicline trial followed identified six trials, covering more than 700 participants, which its participants for 26 weeks. met the inclusion criteria from the Tobacco Addiction Group’s specialised register, in the Cochrane Central Register of Controlled Trials, in June 2008. One study was based on abstracts only, and 4. Anxiolytics 2010 two study authors provided supplementary unpublished data. This review covers any drug with anxiolytic properties, including Participants: beta-blockers. It has been proposed that anxiolytics may help peo- Five trials were set in the community, and one in a hospital clinic. ple to stop smoking, on the basis that anxiety can be a symptom of Four trials targeted heavy smokers, i.e. >20 per day, while one in- nicotine withdrawal, and that smoking could be associated with cluded moderate smokers (>10 per day), and one gave no partici- an attempt to self-medicate an anxiety problem. These treatments pant details. One trial stratified allocation by gender and a history may also appeal to smokers who do not wish to use nicotine-based of depression. Two trials required that participants reduce their medications to make a quit attempt, or who have previously tried baseline smoking by at least 50% at quit date to be admitted to unsuccessfully to quit with NRT. The authors searched the To- the study. Five studies were set in the USA, and one in China. bacco Addiction Group’s specialised register, in the Cochrane Cen- Interventions and comparisons: tral Register of Controlled Trials, in October 2009. They identi- Three trials provided transdermal clonidine in dosages ranging fied one trial each of diazepam, meprobamate, metoprolol and ox- from 0.1 to 0.3 mg per day, and three provided oral clonidine prenolol, and two trials of buspirone (covering 201 participants). with doses ranging from 0.15 to 0.45 mg per day. All the trials A third buspirone trial was not included in meta-analysis since the compared clonidine to placebo, and one also included a diazepam comparators were fixed dose or tapered NRT, rather than placebo. arm. Treatment lasted for four weeks (three trials), six, ten or 12 Participants weeks (one trial each). All the trials used some form of behavioural Adult smokers wanting to quit. One buspirone trial stratified par- support, with four delivering individual counselling sessions for ticipants by high or low anxiety levels, and the authors treated all participants and one a standard counselling message; one trial these separately in the meta-analyses. Apart from the diazepam randomised half of the clonidine and control participants to receive trial set in China and the beta-blockers trial set in Scotland, all the group counselling, but this separation was dropped for the meta- trials were based in the USA. analysis. Interventions and comparisons Outcomes: The buspirone trials compared treatment to placebo; both used The outcome in each trial was abstinence at least 12 weeks from low-dose treatment for 3/4 weeks prior to quit date, and then 60 the end of treatment. Three trials followed up for 12 months, and mg for eight weeks or six weeks. One trial compared four weeks the other three for six months. In the three trials which defined of diazepam to clonidine and to placebo. One study compared abstinence, one selected self-reported 7-day point prevalence, one 40 days of oxprenolol to metoprolol and to placebo, and another relied up self-report through smoking diaries, and one identified tested meprobamate against placebo, with and without different three levels of abstinence, i.e. self-report alone, self-report verified types of counselling. All the trials included a counselling compo- by plasma cotinine but allowing one or two minor lapses in the nent. final week, and lapse-free self-report verified by plasma cotinine. Outcomes Biochemical validation was used systematically by three trials, and One trial measured abstinence at six months, three trials at 12 partially by two more. One trial use no biochemical validation, months, and one defined success as a reduction of more than 85% but sometimes cross-checked with family or co-workers. from baseline smoking rate at 18 months longest follow-up. Two trials used biochemical validation of abstinence, one confirmed self-report by checking with family and co-workers, one gave no 6. Lobeline 2009

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 12 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Lobeline is an alkaloid derived from the leaves of an Indian tobacco cravings. The authors searched the Tobacco Addiction Group’s plant, and has been widely used in commercial smoking remedies. specialised register in January 2009, but identified no trials which Other nicotinic receptor partial agonist compounds have been met the inclusion criteria. shown to be effective aids for smoking cessation (Nicotine receptor Two trials of Nicobrevin were identified, and treated as excluded partial agonists 2012). The authors searched the Tobacco Addic- studies. One followed up only for four weeks, and did not require tion Group’s specialised register in March 2011, but identified no smokers to quit, but used the number of cigarettes smoked at the trials which met the inclusion criteria. Studies generally did not final assessment as the primary outcome. The other trial followed include a control group, and those that did employed a cross-over up for three months, and tested a number of anti-smoking prod- design to measure smoking over days or weeks rather than months, ucts in a single trial. Participants received their allocated therapy and/or did not follow up participants beyond the end of treatment. by post, with the placebo group receiving a placebo matched to the Smoking reduction rather than complete abstinence was the more characteristics of another active therapy rather than to Nicobrevin, commonly used primary outcome. and without validation of self-reported quit rates. Nicobrevin does One multicentre study of sublingual lobeline sulfate tablets with not contribute to any meta-analyses in this overview review. 750 subjects was conducted by Dynagen in 1997. Lobeline does not contribute to any meta-analyses in this overview review. 9. Nicotine vaccines 2012 Nicotine vaccines are not yet licensed anywhere for use as an aid 7. Mecamylamine 2011 to smoking cessation or for relapse prevention. The vaccines are designed to work by blocking nicotine’s access to the brain, re- Mecamylamine, originally marketed for lowering blood pressure, sulting in the smoker deriving less satisfaction when they smoke is a nicotine antagonist, which may block the rewarding effect of a cigarette. It is hypothesised that vaccines may help smokers to nicotine and thus reduce the urge to smoke. The authors searched quit, and may help former smokers not to relapse. The authors the Tobacco Addiction Group’s specialised register in October searched the Tobacco Addiction Group’s specialised register, on- 2010, and identified two small trials, with a total of 128 partici- line clinical trials registers and company websites in March 2012, pants, which met their inclusion criteria. Both trials investigated and identified four trials (2642 participants) which appeared to mecamylamine in combination and in comparison with NRT. meet the inclusion criteria. Only two of the trials, a Swiss study Participants: testing NIC002 and a USA one testing NicVAX, reported their Adult smokers, smoking >1 pack per day. One trial set an upper findings in sufficient detail to contribute to meta-analyses. The age limit of 40, while a second version extended this to 54. two remaining trials, conducted in the USA, also tested NicVAX, Interventions and comparisons: but the manufacturers, Nabi Biopharmaceuticals, have reported The first trial (48 participants) compared mecamylamine capsules no findings beyond a summary quit rate and the lack of a statisti- plus nicotine patch to placebo capsules plus nicotine patch. Each cally or clinically significant difference between the performance group was further divided to begin the patches either two weeks of the active and placebo treatments. before the quit date or coincident with the quit date. The later trial Participants: randomised 80 participants to (1) nicotine patch plus mecamy- Adults, motivated to quit, smoking moderately to heavily (15+ lamine, or (2) nicotine patch alone, or (3) mecamylamine alone, or per day for NicVAX and 10 - 40 per day for NIC002). These two (4) two placebos, no active drug. These regimens applied for four trials covered 642 participants. Information was sparse for the two weeks up to the quit date, after which all groups received nicotine Nabi NicVAX trials, which each included 1000 participants. patch plus mecamylamine for six weeks. Nicotine patch treatment Interventions and comparisons: was faded from 21 mg to 7 mg over the course of treatment, while One trial assigned participants to placebo or to a NicVAX regimen mecamylamine, after initial titration, was administered at 5 mg twice a day, but reducible if not well tolerated. of 200 g or 400 g, and then split each group into a 4-injection Outcomes: or 5-injection schedule over 26 weeks, i.e. four experimental and The first trial measured continuous abstinence to 12 months, and two placebo groups. The two Nabi NicVAX trials delivered six the second continuous abstinence to six months. Validation in both trials was by expired carbon monoxide. injections of 400 g over six months. The Swiss trial assigned participants to a 5-injection schedule of 100 g NIC002 over four months. All the trials provided behavioural counselling through- 8. Nicobrevin 2009 out treatment and follow-up stages. Nicobrevin is a proprietary (off-prescription) product containing Outcomes: 15 mg of quinine, 100 mg of menthyl valerate, 10 mg each of Continuous abstinence was assessed at 26 and 52 weeks for both camphor and eucalyptus oil. It is marketed as an aid to smoking the fully reported trials, and at 52 weeks for the two Nabi trials. cessation, by reducing urges to smoke, withdrawal symptoms and Abstinence was validated by expired CO in all trials, and also by

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 13 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. urinary cotinine in one trial. The Swiss trial and the full USA dependence, ad libitum smoking, cortisol levels and cravings to trial stratiﬁed post-hoc by antibody titer levels, and compared smoke. abstinence and adverse events between the two Ab groups.

11. Rimonabant 2011 10. Opioid antagonists 2009 Selective type 1 cannabinoid (CB1) receptor antagonists, includ- Opioid antagonists, including naltrexone, naloxone and buprenor- ing rimonabant and taranabant, may assist smoking cessation by phine, are long-acting drugs which blunt the effects of narcotics restoring the balance of the endocannabinoid system, which can such as heroin and morphine, and might help reduce nicotine ad- be disrupted by prolonged use of nicotine. They may also address diction by blocking some of the rewarding effects of smoking. The many smokers’ reluctance to persist with a quit attempt because authors searched the Tobacco Addiction Group’s specialised regis- of concerns about weight gain. The authors searched the Tobacco ter in June 2009, and identified two groups of trials for inclusion: Addiction Group’s specialised register in January 2011, and also (1) Four randomised controlled trials, covering 582 participants, contacted the manufacturers of rimonabant. Three trials of rimon- with a minimum follow-up of six months, assessing efficacy for abant were identified for inclusion, covering more than 1700 par- long-term smoking cessation, and (2) 26 randomised controlled ticipants: two measured smoking cessation and one tested relapse trials with short-term follow up that report withdrawal, reinforc- prevention. One trial of taranabant for smoking cessation could ing properties of smoking, or ad libitum smoking. Fourteen of the not be included as it did not assess outcomes beyond eight weeks. 19 naltrexone trials and five small naloxone trials were laboratory- Rimonabant was not licensed for use as a treatment for smoking, based. and production of rimonabant (Sanofi-Aventis) and taranabant For buprenorphine, one was laboratory-based and the other was (Merck) was suspended in 2008, because of concerns about the set in a clinic. type and incidence of adverse events. Participants: Participants: For the four cessation trials, three targeted heavy smokers (a pack Adults, smoking at least 10 cigarettes per day. One trial was set or more a day). One trial aimed at moderate smokers (10 or more in the USA, one in Belgium, Denmark, France, Spain, Sweden, cigarettes a day) reports findings from only one of the four centres Switzerland and the UK, and the relapse prevention trial in Aus- that took part in the trial, with the manufacturers failing to supply tralia, Canada and the USA. the remaining data. Three trials recruited from their communities, Interventions and comparisons: while one recruited from healthcare facilities. All four trials were In the two cessation trials, participants were randomised to receive conducted in the USA. 5 mg, 20 mg or placebo. Treatment was for 12 weeks, and in- The trials delivering short-term findings were all community- cluded regular behavioural support. In the relapse prevention trial, based, apart from those recruiting hospital employees (two trials), participants were initially randomised either to 5 mg or 20 mg for clinic patients (five trials), and heavy drinkers or alcohol-depen- ten weeks to achieve cessation. For phase 2 of the trial, successful dent smokers (two trials). All the trials were set in the USA, apart quitters in the 5 mg group were then randomised to a further 42 from one each in France, Canada, South Korea and the UK. weeks of either 5 mg or placebo regimens; successful quitters in Interventions and comparisons: the 20 mg group were randomised to 42 weeks of 5 mg, or 20 mg, One trial compared four weeks of naltrexone (50-75 mg) to or placebo. This study did not report on the provision or level of placebo. The remaining three cessation trials used naltrexone in behavioural support. combination with nicotine patch. One tested 50 mg of naltrex- Outcomes: one for two months against placebo, with all participants using The two cessation trials measured prolonged abstinence at 50 nicotine patch for one month. Another supplied all participants weeks, validated by expired carbon monoxide and cotinine testing. with nicotine patch added to varying doses (100, 50 and 25 mg) The relapse prevention trial scheduled measures of time to relapse of naltrexone, compared to placebo for six weeks. The third tested up to 52 and 104 weeks, although the two-year outcome was not naltrexone alone (50 mg for 12 weeks) against nicotine patch with been reported. One-year outcomes were validated by expired car- placebo pill, naltrexone with nicotine patch, and placebo pills bon monoxide. Weight change was also assessed throughout the alone. All four trials included a counselling component. study period in all three trials. Outcomes: All four cessation trials measured continuous abstinence at six months, with one also measuring point prevalence abstinence at 12. Silver acetate 2009 12 months. Three of the four validated outcomes by expired car- Silver acetate, in gum, lozenge, and spray formulations, creates an bon monoxide, while one verified by testing plasma cotinine. unpleasant metallic taste when combined with cigarettes, thereby Short-term outcomes included number of cigarettes smoked per producing an aversive stimulus. It has been marketed in various day, withdrawal symptoms, positive and negative affect, nicotine forms with the aim of extinguishing the urge to smoke, by pairing

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 14 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. the urge with an unpleasant stimulus. The authors searched the Antidepressants 2007 (i.e. no clear evidence of publication bias), Tobacco Addiction Group’s specialised register in January 2009, and a lack of published studies with negative findings for Nicotine and identified two trials of silver acetate for long-term smoking receptor partial agonists 2012. However, as the varenicline studies cessation, covering almost 1000 participants. are routinely included in online clinical trials registers before the Participants: trials begin, in the interests of reporting transparency, consistent Adults smoking more than 10 cigarettes a day, motivated to quit. direction of effect may be as plausible an interpretation as failure One trial was set in the USA, and the other in Denmark. to disclose negative or unfavourable study findings. Interventions and comparisons: One estimate of the quality of the included studies in the 12 re- The USA trial supplied participants with 2.5 mg lozenges, to be views, measured by their risks of bias, is briefly summarised in taken six times a day for three weeks, versus placebo lozenges. Table 4. Newer studies are more likely to be conducted in accor- Successful quitters were given further supplies to assist with relapse dance with CONSORT guidelines and to report their method- prevention. The Danish trial compared six weeks of 6 mg silver ology more rigorously than earlier trials, but there remains great acetate gum (up to six pieces a day) to 2 mg nicotine chewing gum variation between trial methods and standards of reporting. or ordinary chewing gum (placebo). This trial was not blinded. Outcomes: Both trials tested sustained abstinence at 12 months, validated by Effect of interventions expired carbon monoxide; one also used urinary cotinine testing to validate outcomes. Efficacy network meta-analyses (NRT, bupropion, varenicline) The reviews covering NRT, bupropion and varenicline showed Methodological quality of included reviews them all to increase the chances of quitting compared with placebo. AMSTAR ratings for the included reviews are summarised in Table The estimated effect sizes are reported in the source reviews as 2 (NRT, bupropion, nortriptyline, varenicline and cytisine) and risk ratios, and are given for reference in Appendix 3. Appendix 1 in Table 3 (other pharmacotherapy reviews). All 12 reviews were tabulates the binary meta-analyses from the relevant reviews (con- classified as being of high quality, i.e. failing to score in only verted to odds ratios) against the corresponding network meta- two or fewer of the 11 domains. Two reviews (Lobeline 2009; analyses. The findings reported below are based on network meta- Nicobrevin 2009) did not have any included studies, and a third analyses using the same data sets, and estimate the effect sizes as review (Mecamylamine 2011) did not conduct meta-analyses, and odds ratios, in accordance with the Bayesian model used in the therefore could not be assessed for the relevant domains. Eight re- analyses. views combined the publication of the protocol and the full review The first network meta-analysis for smoking cessation shows that as a single document, and therefore did not present the ’a priori’ the odds of quitting are significantly increased for those taking design in advance of the review findings. All eight were originally NRT or bupropion over those taking placebo. The odds ratio (OR) published between 1996 and 1998, apart from Nicobrevin 2009, for NRT versus placebo is 1.84; 95% credible interval (CredI) which first appeared in 2006. The other consistent shortfall was 1.71 to 1.99, and for bupropion versus placebo 1.82; 95% CredI in the domain of publication bias. Two reviews did not include 1.60 to 2.06. Varenicline was shown to further increase the odds of any eligible studies (Lobeline 2009; Nicobrevin 2009), and one quitting compared with placebo, with an OR of 2.88; 95% CredI had included studies but without peer-reviewed or published data 2.40 to 3.47. (Rimonabant 2011). Five reviews did not generate funnel plots or The comparison between bupropion and NRT suggests no advan- address the likelihood of publication bias in the text. Three of the tage for either treatment, with an OR of 0.99; 95% CredI 0.86 five (Anxiolytics 2010; Clonidine 2008; Opioid antagonists 2009) to 1.13. Varenicline is shown to be superior both to NRT(OR had too few included studies to support a formal assessment of 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% publication bias. Ad hoc generation of funnel plots for the remain- CredI 1.29 to 1.96). We found no evidence that the consistency ing two reviews indicated a broadly symmetrical distribution for assumption was not met. (Figure 2).

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 15 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 2. Network meta-analysis of smoking cessation with each ﬁrst-line pharmacotherapy versus placebo and versus each other

The probability of treatment ranking plot gives an indication of how the treatments are ranked in terms of efﬁcacy. Varenicline has a probability of being ranked ﬁrst equal to 1, meaning that in the 40,000 MCMC samples, varenicline was the most effective treatment in all 40,000 samples. NRT was estimated to be the second best treatment in around 23,200 (58%) of the samples, and hence has a probability of being ranked second of 0.58. Bupropion was the second best treatment in the remaining 16,800 (42%) samples and hence has a probability of being ranked second of 0.42. Placebo was estimated to be the least effective in all of the 40,000 samples, hence it is ranked fourth with probability equal to 1 (Figure 3).

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 16 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Distribution of probabilities of each treatment being ranked at each of the four possible positions for smoking cessation

The second network meta-analysis split NRT into four subgroups: patch, gum, combination NRT and “other” NRT (i.e. in- to 1.87), compared with NRT gum (OR 1.72; 95% CredI 1.38 halers, sprays, tablets and lozenges). We excluded trials that gave to 2.13), and compared with ’other’ NRT (OR 1.42; 95% CredI patients a choice of NRT either in the intervention or control 1.12 to 1.79), but was not more effective than combination NRT arm. The four NRT categories, bupropion and varenicline were (OR 1.06; 95% CredI 0.75 to 1.48). The four types of NRT per- all compared with placebo and with each other (Figure 4). All six formed similarly against each other, apart from ’other’ NRT, which treatments significantly increased the odds of quitting when com- was marginally more effective than NRT gum (OR 1.21; 95% pared to placebo. Varenicline significantly increased the odds of CredI 1.01 to 1.46). As with the first meta-analysis, we found no quitting compared with NRT patch (OR 1.51; 95% CredI 1.22 evidence of inconsistency.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 17 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 4. Network meta-analysis of ﬁrst-line pharmacotherapies versus placebo and versus each other, with NRT split by type

From the Antidepressants 2007 binary meta-analyses, and not included in the network meta-analysis, bupropion combined with only side effect that appears to interfere with use of the patch NRT was not shown to be more effective than NRT alone (RR is skin sensitivity and irritation; this may affect up to 54% of 1.23, 95% CI 0.67 to 2.26; six trials). patch users, but it is usually mild and rarely leads to withdrawal of patch use (Fiore 1992). Nicotine inhalers and nasal and oral sprays may lead to mild or moderate local irritation at the site of Adverse events and Serious Adverse Events (SAEs) administration . For nasal spray, nasal irritation and runny nose are For the purposes of the source reviews, adverse events that were the most commonly reported side effects. In the study of oral spray, life-threatening or resulted in death, hospitalisation, signiﬁcant hiccoughs and throat irritation were the most commonly reported disability or birth defect were considered to be SAEs, whether or adverse events (Tønnesen 2012). Nicotine sublingual tablets have not the trialists attributed them to use of the medication (Tonstad been reported to cause hiccoughs, burning and smarting sensation 2010). We have not included NRT in our analyses, as coverage of in the mouth, sore throat, coughing, dry lips and mouth ulcers SAEs is either sparse or entirely absent from the trial reports. (Wallstrom 1999). NRT Reviews and trials exploring the incidence of adverse events among Adverse events people with cardiac disease have found no excess or increased risks ( There was extensive variation in reporting the nature, timing and Greenland 1998; TNWG 1994; Joseph 1996; Joseph 2003; Meine duration of symptoms. The major side effects usually reported with 2005). The four trials assessing NRT use in pregnant women did nicotine gum include hiccoughs, gastrointestinal disturbances, jaw not detect signiﬁcant increases in serious adverse events amongst pain, and orodental problems (Fiore 1992; Palmer 1992). The the treatment groups. Recruitment for Pollak 2007 was suspended

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 18 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. early when interim analysis found a higher rate of negative birth In the UK, France and Australia (countries in which bupropion outcomes in the NRT arm; however, when adjusted for previous is licensed only for smoking cessation), it has been implicated in birth outcomes the adverse event rate between the two groups was reports of suicidal ideation and suicidal behaviour, with reported not significantly different in final analysis. event rates in the order of 1:10,000 (MHRA 2004, TGA 2004, Despite NRT’s safety record, a recent meta-analysis of adverse Beyens 2008). A review of bupropion’s safety, undertaken by the events associated with it (Mills 2010) across 92 RCTs and 28 European Agency for the Evaluation of Medicines for Human Use observational studies has raised questions about a possible excess of (EMEA 2002) identified six cases of suicidal ideation among 4067 chest pains and heart palpitations among users of NRT compared trial participants, and commented that the rate was lower than with placebo groups. The authors calculate an OR of 2.06; 95% that found in the general population, but without providing sup- CI 1.51 to 2.82 across 12 studies. We replicated this data collection porting data. The committee stated that they found no pharma- exercise and analysis across 260 included and excluded studies in cological or clinical reason for suspecting that bupropion could be the NRT review, where such data were reported. We calculated causally associated with depression or suicide. However, they rec- a similar but slightly lower estimate across 15 studies, OR 1.88; ommended strengthening warnings to clinicians on the possibility 95% CI 1.37 to 2.57 (expressed as an odds ratio for comparability of hypersensitivity and of depression in patients taking bupropion with the Mills point estimate). In our estimation, this is potentially for smoking cessation. the only clinically significant adverse event to emerge from the A follow-up study of 136 women who had taken bupropion dur- trials, and constitutes an extremely rare event, occurring at a rate ing the first trimester of pregnancy detected no increase in major of 2.5% in the NRT group compared with 1.4% in the control malformations, but reported a significant increase in spontaneous group in the 15 trials in which it was reported at all. This finding abortions (Chun-Fai-Chan 2005). Bupropion is also an inhibitor should be treated with caution, because of wide disparities in the of CYP2D6, so care is needed when starting or stopping treatment scale and type of reporting of adverse events across the trials. for patients taking other medication metabolised by this route Serious Adverse Events (Kotlyar 2005). Little or no information on SAEs was provided in the trial reports. In 2004, the US Food and Drug Administration (FDA) issued Bupropion warnings for several antidepressants, including bupropion, when Adverse events used to treat depression. In 2009 this warning was extended to the The most common adverse events reported for bupropion in the use of bupropion for smoking cessation, suggesting that it might trials were insomnia, occurring in 30% to 40% of patients, dry be associated with serious neuropsychiatric symptoms (USFDA mouth (10%) and nausea. Typical drop-out rates due to adverse 2009a). This followed 46 reports of suicidal ideation and 29 of events ranged from 7% to 12%. The trials also report the occur- suicidal behaviour from 1997 to November 2007. It remains un- rence of allergic reactions, including pruritus, hives, angioedema clear what relationship, if any, exists between these events and con- and dyspnoea, at rates of about 1 to 3 per 1000, an incidence rate comitant use of bupropion. in line with post-marketing surveillance data (GlaxoSmithKline). For this overview, we have conducted meta-analyses of SAEs re- National surveillance schemes also contain case reports of arthral- ported in the 49 included and 33 excluded trials of bupropion, gia, myalgia, fever with rash, and other symptoms suggestive of based on all participants randomised. Meta-analyses of 21 bupro- delayed hypersensitivity linked to bupropion use, but it is not pos- pion trials (included and excluded) which reported any SAEs while sible to determine frequency rates from these sources. on treatment found a marginal but statistically non-significant ex- Serious Adverse Events: cess of events in the bupropion groups compared with the placebo The main serious adverse event (SAE) for bupropion was seizures, groups (RR 1.29; 95% CI 0.99 to 1.69; 7859 participants). The which may occur at a rate of around 1:1000 users. This risk ap- event rates for any SAE were 2.5% for bupropion and 2.2% for peared to be reduced for the sustained-release formulation, given placebo users. Subgroup analysis of neuropsychiatric SAEs de- at dosages of 300 mg or less a day, and excluding those with a tected no difference between the bupropion and placebo arms, history of seizures, with eating disorders, or with a personal or with an RR of 0.88, 95% CI 0.31 to 2.50 (six trials). The event family history of epilepsy. This incidence rate is reflected in pre- rates were 0.8% and 0.9% respectively. Subgroup analysis of car- scription-event monitoring studies, observational studies and na- diovascular events detected no difference between the two groups, tional surveillance databases in the UK and Canada (Dunner 1998, with an RR of 0.77; 95% CI 0.37 to 1.59 (ten trials) and event Boshier 2003, Hubbard 2005). A report to the US Toxic Exposure rates of 0.3% for bupropion and 0.5% for placebo. Surveillance System (1998-9), covering accidental and intentional Although we tallied reports of seizures across the trials, there were overdoses and adverse effects of bupropion, noted that 6% of ex- too few to support a meaningful meta-analysis. Four trials reported posure events led to a seizure, with highest rates associated with six seizures in the bupropion arms, and a further two reported Welbutrin (immediate release formulation), and lowest with Zy- one seizure each in the open-label pre-randomised populations, ban (sustained release). Bupropion is not recommended for people all of whom at that stage were either taking bupropion alone or with a history of seizures. bupropion plus NRT. No seizures were reported for any of the

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 19 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. placebo participants. Twenty-five bupropion trials gave sufficient atric events (FDA 2011). One study, conducted by the Depart- detail on SAEs to be included in the meta-analyses (including ment of Veterans’ Affairs, examined the incidence of psychiatric seizures data), two reported total SAEs across all participants (data hospitalisations in 14,131 varenicline users versus an equal number not usable), 15 trials reported that no SAEs occurred, while the of NRT users; at 30 days post-prescription, they found no statisti- remaining trials provided no information. cally significant difference in the risk of this outcome, with a Cox Varenicline proportional hazard ratio for varenicline/NRT of 0.76 (95% CI Adverse events 0.40 to 1.46). The second FDA-sponsored study was conducted The main adverse event for varenicline was nausea, generally at by the Department of Defence, in a propensity-matched cohort of mild to moderate levels and subsiding over time. Titration, self- 10,814 varenicline users and the same number of NRT users. This regulation of dosage and lower dosages tended to reduce the in- study also found no excess of psychiatric hospitalisations at 30 or cidence. Attributable discontinuation rates ranged from 0.6% to 60 days for either group; the hazard ratio for varenicline/NRT was 7.6%. Participants also experienced raised levels of insomnia, ab- 1.14 (95% CI 0.56 to 2.34) (Meyer 2013). While these studies normal dreams and headache. In the two seminal Phase III trials cannot be assumed to have captured all relevant data, e.g. adverse (Gonzales 2006; Jorenby 2006), an average of 9.5% in the vareni- events that did not lead to an inpatient episode, they nonetheless cline groups discontinued treatment but remained in the trial for represent substantial cohorts of people in a real-world setting with follow-up, compared with an average of 14% in the bupropion a range of comorbidities, and with findings consistent between the groups and 8% in the placebo groups. Discontinuation rates for two studies. any adverse event were highest in Williams 2007, where partici- The FDA issued a Drug Safety Communication warning in 2011, pants took the trial medication for a year, at 28.3% in the vareni- following publication of a trial of varenicline in patients with cline group and 10.3% in the control group. stable cardiovascular disease (Rigotti 2010), although the trial- Serious Adverse Events ists themselves concluded that varenicline was well tolerated and Meta-analyses of any SAE while on or immediately after treatment was not associated with increases in cardiovascular events, deaths, (usually within one week or one month) in those who took at blood pressure, or heart rate. A meta-analysis of 14 trials (Singh least one dose of varenicline compared to those on placebo did not 2011) detected an increased risk of serious cardiovascular events detect any excess of events: RR 1.06 (95% CI 0.72 to 1.55; 14 for varenicline users, with a Peto odds ratio of 1.72; 95% CI 1.09 trials, 6333 participants). The event rates for any SAE were 2.1% to 2.71; however, this analysis may have some methodological in the varenicline arms and 2.0% in the placebo arms. Subgroup flaws and limitations which could weaken the conclusions that analysis restricted to neuropsychiatric events found no difference the authors draw from their findings. A subsequent systematic re- between varenicline and placebo users: RR 0.53 (95% CI 0.17 to view and meta-analysis of 22 varenicline trials (Prochaska 2012), 1.67), with event rates of 0.15% for varenicline and 0.21% for restricted to events within the period of drug treatment plus 30 placebo arms respectively. The subgroup analysis for cardiovascular days and presenting four summary measures (risk difference, risk events identified no difference between the two arms: RR 1.26 ratio, Mantel-Haenszel and Peto odds ratios), detected neither a (95% CI 0.62 to 2.56), with event rates of 0.6% and 0.5% for clinically nor a statistically significant excess for the varenicline varenicline and placebo respectively. Sensitivity analyses excluding users. A prescription-event monitoring study of almost 16,000 from the denominator those who had not completed treatment people prescribed varenicline in New Zealand between April 2007 made no difference to our findings. and November 2010 (Harrison-Woolrych 2012) identified 172 Post-marketing surveillance has raised concerns about possible cardiovascular adverse events. Among these cases 48 were classi- links between varenicline use and neuropsychiatric or cardiac fied as myocardial Ischaemic events, and 50 as hypotensive events. events. In 2008, the FDA required the manufacturers of vareni- Within each of these subgroups, two cases were considered by the cline to include a boxed warning on the packaging, to alert users investigators to have possibly been triggered by varenicline use. and clinicians to the possibility of increased risks of behaviour However, despite these areas of uncertainty, the FDA concludes change, agitation, depressed mood, and suicidal ideation and be- that “the Agency continues to believe that the drug’s benefits out- haviour. Tonstad 2010, a meta-analysis of the incidence of psychi- weigh the risks and the current warnings in the Chantix drug label atric adverse events in ten completed RCTs of varenicline, found are appropriate” (FDA 2011). no excess of events apart from sleep disorders, with an RR of 1.02 (95% CI 0.86 to 1.22). A UK cohort study (Gunnell 2009) and prescription-event monitoring studies in the UK (Kasliwal Cytisine: efficacy, adverse events and serious adverse events 2009) and in New Zealand (Harrison-Woolrych 2011) have not The two recent cytisine trials measured continuous abstinence, detected significantly raised incidence rates of depression or of sui- biochemically confirmed at longest follow-up. The RR was 3.98; cidal ideation and behaviour. 95% CI 2.01 to 7.87. The 1971 cytisine trial used self-reported The FDA has sponsored two retrospective cohort studies, to ex- point prevalence abstinence at two years, yielding an RR of 1.61; plore possible relationships between varenicline and neuropsychi- 95% CI 1.24 to 2.08.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 20 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. None of the trials reported any serious adverse events associated higher quit rates than the intervention groups. One beta-blocker with cytisine. A recent trial reported 10 events in eight participants trial found a cessation rate at 12-month follow-up of 17% for ox- (four from each group), including dyspepsia, nausea and headache, prenolol, 24% for metoprolol and 3% for placebo. The difference while the other reported gastrointestinal disorders at higher rates was statistically significant for metoprolol but not for oxprenolol. in the cytisine than in the placebo group (13.8% vs 8.1%, P = However the marked difference between the groups on active drug 0.02) and placebo developed after the end of drug treatment, which is surprising. The review notes that many of the anxiolytics have significant side Nortriptyline: efficacy, adverse events and serious adverse effects such as a risk of abuse or dependence, and sedation. In view events of uncertain efficacy and the side effects of the drugs, there is little Six trials comparing nortriptyline with placebo detected a risk ratio justification for using them. (RR) of 2.03; 95% confidence interval (CI) 1.48 to 2.78, in favour Clonidine 2008 of the treatment; however, four trials testing it as an adjunct to Six studies meeting the inclusion criteria favoured clonidine treat- NRT did not demonstrate an unequivocal benefit for the addition ment, although only one reached a statistically significant con- of nortriptyline (RR 1.29; 95% CI 0.97 to 1.72). clusion. Combining the results of the six studies gives a pooled Adverse events for nortriptyline included dry mouth, drowsiness, RR of 1.63; 95% CI 1.22 to 2.18, suggesting that clonidine is light-headedness and constipation, observed in studies treating de- effective. This equates to an absolute increase in the likelihood of pression in which doses were often > 150 mg. Nortriptyline for quitting using clonidine of about 9%, given the quit rate amongst smoking cessation was generally prescribed at lower doses, with the pooled control groups of 14%. drop-out rates ranging from 4% to 12%, which is similar to that Clonidine has clinically significant symptoms of sedation and pos- for bupropion and NRT. The only serious adverse event in some- tural hypotension occurring in a dose-dependent manner in par- one treated with nortriptyline was collapse/palpitations, thought allel with efficacy. it is reasonable to consider oral or transdermal possibly to have been caused by treatment. clonidine as a second-line pharmacotherapy for smoking cessation, but close medical supervision is essential to titrate the dose appropriately and monitor for potentially severe adverse effects. Efficacy, adverse events and serious adverse events of other Lobeline 2009 treatments: There were no studies which met the inclusion criteria. At six-week follow-up in the Dynagen 1997 study, there was no statistically Antidepressants 2007 significant difference in quitting between placebo (15% abstinent) The efficacy, adverse events and serious adverse events for bupro- and lobeline (17%). pion and nortriptyline are covered in the sections above. Adverse events for lobeline include dizziness, nausea and vomit- Among the SSRIs, there was no evidence of clinically significant ing,and tablets and pastilles containing lobeline may cause throat benefit of using fluoxetine (four trials; RR 0.92; 95% CI 0.68 to irritation. 1.24), or for paroxetine (one trial: RR 1.08; 95% CI 0.64 to 1.82), Mecamylamine 2011 or for sertraline (one trial; RR 0.71; 95% CI 0.30 to 1.64). The review authors considered that the data from two small trials In the MAOI group of drugs, one trial of moclobemide demon- were insufficient to support a meta-analysis, and relied upon re- strated efficacy at the six-month assessment, but this had dissi- porting quit rates and P values. In the first included study, the com- pated by 12 months (RR 1.57; 95% CI 0.67 to 3.68). Three trials bination of mecamylamine capsules and nicotine patches com- of selegiline did not detect a benefit of treatment (RR 1.45; 95% pared to nicotine patches and placebo capsules led to a statistically CI 0.81 to 2.61), and demonstrated significant heterogeneity (I² significant difference in rates of sustained abstinence at six months = 55%). (37.5% versus 12.5%, P = 0.046) and at 12 months (37.5% versus Anxiolytics 2010 4.2%, P = 0.004). In the second study, the reported rates of sus- Two trials comparing buspirone with placebo yielded a RR of tained abstinence at six months were 40% in the group pre-treated 0.76; 95% CI 0.42 to 1.37. The point estimate does not estab- with nicotine + mecamylamine, 20% in the group treated with lish effectiveness, but the confidence intervals do not rule out a nicotine alone, and 15% in the groups treated with mecamylamine clinically useful effect. One of the trials found a significant benefit alone, and with no drug treatment. The higher rate of abstinence of buspirone among the high anxiety subjects at the end of drug in the group pre-treated with nicotine and mecamylamine was not therapy (88% versus 61%, P < 0.01). However, the other trial did statistically significant. The authors detected a significant bene- not replicate this effect. fit for the two groups receiving mecamylamine prior to cessation One trial each of diazepam and meprobamate found no statistically compared to the groups which did not. or clinically significant effect of either drug. The meprobamate Mecamylamine can have significant adverse effects, including trial took an 85% or greater reduction as its outcome rather than drowsiness, hypotension and constipation. In the first study, 70% complete abstinence, and found that the placebo groups produced

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 21 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. of subjects treated with mecamylamine reported constipation the NicVAX trial (95% CI 1.34 to 5.22). However, at 12 months compared to 30% treated with placebo, and two subjects required the difference in abstinence between low and high Ab groups in a dose reduction. In the second study, 40% of subjects required a the NicVAX trial was no longer statistically significant (RR 1.80; reduction in dose of mecamylamine. 95% CI 0.81 to 3.99). Nicobrevin 2009 The two studies with full results showed nicotine vaccines to be Neither of the identified trials met the inclusion criteria, and both well tolerated, with the majority of adverse events classified as would have had some methodological concerns. In one, the smok- mild or moderate. In the NIC002 trial, participants receiving the ers were not asked to try to quit, and numbers of cigarettes smoked vaccine were more likely to report mild to moderate adverse events, on the last day of therapy was the primary outcome. Levels of most commonly flu-like symptoms, whereas in the NicVAX trial blood carbon monoxide were measured, but not related to smok- there was no significant difference between the two arms. Findings ing status so could not be used to validate self-reported quitting. on adverse events were not available for the two large Phase III In the second study, a variety of smoking cessation products were trials of NicVAX, although the treatment was described in a Nabi tested in a single trial. Participants received their allocated therapy press release as “ well-tolerated with a clinically acceptable safety by post. The placebo group received a placebo matched to the and tolerability profile”. characteristics of another active therapy rather than to Nicobrevin, Opioid antagonists 2009 and there was no validation of self-reported quit rates. Four trials of naltrexone did not detect a significant effect of the in- In April 2011, the Medicines and Healthcare products Regula- tervention over placebo for long-term abstinence, with or without tory Agency (MHRA) published a public assessment report on NRT supplementation. The RR was 1.21; 95% CI 0.83 to 1.77. Nicobrevin. They determined that efficacy is unproven, that none The review includes a further 24 trials, which assessed withdrawal of the UK smoking cessation agencies recommend its use, and symptoms, ad libitum smoking and hedonic effects, without con- that the possibility of side effects associated with the quinine and tributing to the abstinence data. camphor components had led them to the view that the risks of The review did not report the incidence or severity of any adverse Nicobrevin outweighed its benefits. They therefore withdrew its events. UK license from January 31st 2011 (MHRA 2011). This decision Rimonabant 2011 post-dates the latest update of the Nicobrevin review. The two cessation trials detected an RR of 1.50; 95% CI 1.10 to Nicotine receptor partial agonists 2012 2.05, favouring rimonabant 20 mg over placebo. No significant The efficacy, adverse events and serious adverse events for vareni- benefit was demonstrated for rimonabant at 5 mg dosage. In the cline and cytisine are covered in the sections above. relapse prevention trial, smokers who had quit on the 20 mg reg- The dianicline trial did not demonstrate a significant effect, imen were more likely to remain abstinent on either of the active measuring continuous abstinence biochemically confirmed at six regimens than on placebo; the RR for the 20 mg maintenance months, with an RR of 1.20; 95% CI 0.82 to 1.75. This trial, EU- group was 1.29; 95% CI 1.06 to 1.57, and for the 5 mg mainte- RODIAN, based in six European countries, was one of two con- nance group 1.30; 95% CI 1.06 to 1.59. There appeared to be no ducted by its manufacturers, Sanofi-Aventis. We have been unable significant benefit of maintenance treatment for those who had to obtain trial information or results for the USA-based compan- quit on 5 mg. ion trial, AMERIDIAN. The drug is no longer in development. Adverse events included nausea and upper respiratory tract infec- Nicotine vaccines 2012 tions, but little information was provided. None of the four included studies detected a statistically significant Silver acetate 2009 difference in long-term cessation between participants receiving The first trial, comparing silver acetate gum with nicotine gum or vaccine and those receiving placebo. For the NIC002 trial, the RR with ordinary gum, found no significant differences in smoking was 1.35 (95% CI 0.82 to 2.22), and for the NicVAX trial the RR status between the silver acetate and NRT arms (RR 0.98; 95% was1.74; 95% CI 0.73 to 4.18. The two Phase III NicVAX trials, CI 0.69 to 1.39). The second trial, comparing silver acetate with for which full results were not available, reported similar quit rates placebo lozenges also failed to detect a significant effect, with an of approximately 11% in both intervention and placebo groups in RR of 1.04; 95% CI 0.69 to 1.57. the first trial, and results that were “not different” in the second. In both trials, the total dose of silver acetate was restricted to In the two studies with full results available, post hoc analyses de- reduce the chance of developing the rare outcome of argyrism tected higher cessation rates in participants with higher levels of (silver deposition in body tissues), and no subject suffered this nicotine antibodies, but these findings are not readily generalis- side-effect. The main adverse effects reported were those expected able. At six months, subgroups with high levels of antibody (Ab) from this aversive stimulus; unpleasant tastes and sensations in the titer in both studies demonstrated statistically significantly higher mouth, and gastrointestinal disturbances. continuous abstinence rates than groups with lower Ab levels, with an RR of 1.76 in the NIC002 trial (95% CI 1.23 to 2.54, high Ab vs low + medium Ab groups combined) and an RR of 2.65 in

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 22 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DISCUSSION a number of observational studies and challenged by others, the evidence is inconclusive at present, and long-term post-marketing We have placed particular emphasis in this overview upon the surveillance will continue to inform the debate. three most widely used pharmacotherapies. These are also the most Among other treatments, clonidine also appears to be effective, but comprehensive of the pharmacotherapy reviews in this area; the this is offset by a dose-dependent rise in adverse events. Mecamy- nicotine replacement therapy (NRT) review covers 150 included lamine in combination with NRT may increase the chances of studies, the antidepressants review includes 49 studies of bupro- quitting, but the current evidence is inconclusive. Cytisine re- pion and nine of nortriptyline, and the nicotine receptor partial turns positive findings, without significant adverse events or SAEs. agonists review covers 20 included studies of varenicline and three Other treatments subjected to meta-analysis within the reviews fail of cytisine. We have conducted network meta-analyses of the effi- to demonstrate a statistically or clinically significant benefit com- cacy of NRT, bupropion and varenicline, versus placebo and ver- pared with placebo. Nicotine vaccines are not yet licensed for use sus each other, and have also used conventional meta-analyses to as an aid to smoking cessation or relapse prevention. Nicobrevin’s explore the serious adverse event profiles of bupropion and vareni- UK license is now revoked, and the development of rimonabant, cline. The remaining treatments are examined through a combi- taranabant and dianicline have all been suspended by their man- nation of narrative and statistical evaluations. ufacturers.

Summary of main results Overall completeness and applicability of This overview identified 12 Cochrane reviews of pharmacother- evidence apies used to assist smoking cessation. Three treatments (NRT, bupropion and varenicline) are licensed as aids for smoking ces- The completeness of an overview is necessarily limited by the re- sation in high-income countries and recommended by many na- cency of the source reviews. For NRT, bupropion and varenicline, tional guidelines, and we have concentrated on these interventions while NRT 2012 and Nicotine receptor partial agonists 2012 are for this overview. currently up to date, Antidepressants 2007 (covering bupropion Both NRT and bupropion are similarly effective compared with and nortriptyline) has not been updated since 2009. Two bupro- placebo in helping people to quit. Varenicline is more effective pion trials derived from the excluded reviews which are not covered than NRT or bupropion, when compared with placebo. in Antidepressants 2007 have both been published since that re- Direct and indirect comparisons between the three treatments view was last updated. This means that the contributing evidence demonstrate no advantage for NRT over bupropion. Varenicline is for bupropion is out of date compared with the other two inter- shown to be superior to any single type of NRT and to bupropion. ventions. A further four reviews (Clonidine 2008; Lobeline 2009; Different types of NRT are generally equally effective. Combina- Opioid antagonists 2009; Silver acetate 2009) are at least one year tions of NRT outperform single formulations, and may be as ef- beyond the optimum 2½-year update cycle. Opioid antagonists fective as varenicline. None of the network meta-analysis findings 2009 is currently being updated, and we are not aware of any show evidence of inconsistency. randomised controlled trials awaiting evaluation for the other Cytisine (pharmacologically similar to varenicline) also increases three reviews. However, there remains a possibility that out-of- the chances of quitting compared with placebo. date reviews may compromise the stability and completeness of Nortriptyline increases the chances of quitting compared with the overview findings. placebo. NRT combined with nortriptyline or with bupropion is The NRT and bupropion trials in this overview span a longer pe- not shown to be more effective than NRT alone. riod (from 1979 and 1992 respectively) than the varenicline stud- There is a known risk of seizures in people taking bupropion, ies (2006 onwards), and they include a higher proportion of non- at a rate of about 1:1000, and probably lower than this for the industry studies (Etter 2007). One factor in the apparently lower slow-release formulation. Our estimate of six seizures across all efficacy of NRT and bupropion compared with varenicline may the bupropion arms is lower than the expected rate, at about 1: be associated with the mix of smaller trials of lower quality, and 1500. Our meta-analyses of serious adverse events (SAEs) in the the more varied settings and populations typical of older trials, bupropion studies demonstrate no excess of neuropsychiatric or which could be expected to reduce the point estimate. However, cardiovascular events for bupropion users. These findings, while as pragmatic trials of community-based or disease- or age-specific reassuring, may not be as robust as the efficacy results, since data populations have accrued to the varenicline review, the point esti- on SAEs may have been under-reported, especially in earlier trials. mate has remained relatively stable, maintaining a two- to three- Varenicline’s superior efficacy must be tempered by current ques- fold increase in the chances of quitting. The robustness of effect tions about its safety. Meta-analysis of any SAE while on vareni- as the evidence base expands lends further support to varenicline’s cline compared with placebo finds no difference between them, advantage as an aid to cessation. and subgroup analyses detect no significant excess of neuropsychi- We report on two recent trials of cytisine, which are covered in atric or cardiovascular events. While this finding is supported by the Nicotine receptor partial agonists 2012 review. The success of

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 23 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. varenicline has focused attention on its predecessor, Tabex [cyti- tionately positive findings (Scherer 2007). Approximately 10% of sine], which was developed in Bulgaria during the 1960s, and is trials referenced in Cochrane reviews are taken from conference widely available in Russia and the former socialist economy coun- proceedings and other grey literature sources (Mallett 2002). tries, and as an internet commodity. Although it is not licensed The remaining treatments were generally limited to small studies, for use within the European Union or the USA, its potential as an frequently with inadequate or no description of the methodolog- affordable and effective smoking cessation treatment has sparked ical features used to estimate study quality. Only five treatments interest in further testing and development (Hajek 2013). A trial within this category assessed populations of more than 1,000 par- of Tabex versus NRT was registered in 2010, aiming to recruit ticipants. Fluoxetine (1236 participants in two trials) was not 1310 smokers in New Zealand, but we are not aware of any other shown to improve cessation rates, and nortriptyline (1219 partic- ongoing research in this area, so the gaps are likely to be in the ipants in four trials) did not enhance the performance of NRT. funded research agenda rather than in the overview’s coverage of The efficacy of rimonabant (1049 participants across two trials) this treatment. and NicVAX (2000 participants across two trials) could not be While the evidence base for the efficacy of treatments may be conclusively demonstrated, since the findings came from abstracts considered adequate, information on adverse and serious adverse and company reports rather than from published papers. Cyti- events is generally less well reported. We have not included NRT sine (2151 participants in three trials) demonstrated a significant in our meta-analyses of SAEs, since coverage of this information effect, although the study which contributed more than half the was patchy or absent from many trial reports. It was often not participants was the oldest and the least adequately conducted and clear whether this could be ascribed to the lack of such events reported. or to under-reporting and/or misattribution. Recent studies have tended to report SAEs more comprehensively, to the benefit of the bupropion and varenicline evidence bases. However, much of Potential biases in the overview process the information that has caused concern over the safety profile of There are a number of potential sources of bias within the overview these treatments has emerged from monitoring and surveillance process. We have confined ourselves to Cochrane reviews, on the programmes rather than from trial reports. An evaluation of safety assumption that they represent the most comprehensive and co- based on trial reports would require substantial sample sizes of herent body of evidence available. An associated potential weak- real-world heterogenous populations, perhaps supplemented by ness is that three of the authors of this overview (KC, RP,TL) have analyses of individual patient data and expert clinical assessment. contributed to most of the included reviews, either explicitly as authors or implicitly during the editorial processes. To counter- balance this, we have attempted to assess the quality and limita- Quality of the evidence tions of the included reviews as rigorously as possible, using inde- Although the quality of the included reviews in this overview is pendent and objective criteria, including the modified AMSTAR considered to be high (based on AMSTAR ratings), the quality scale; but it is still possible that we have introduced biases by being of the trials covered within individual reviews is variable. Across insufficiently distanced from the review/overview process. the board, older trials tended to under-report their methodology. Our preference for intention-to-treat analyses may have intro- While increased online publication and the CONSORT 1996 duced bias into our methods for handling missing data. The seri- statement have partially addressed this situation, the conduct of ous adverse events analyses for varenicline and bupropion include the trials may not necessarily have improved in line with reporting all participants randomised who were known to have received at standards. least one dose of treatment, whether or not we had follow-up data For the three network meta-analysis treatments, the newest, vareni- for them on these events. Our assumption has been that, provided cline, maintained the highest study quality, with 81% of trials there are no great disparities between rates of attrition from the estimated to be at low risk of bias for their randomisation pro- intervention and control groups, missing data are unlikely to mis- cedures (sequence generation and allocation concealment). This represent the relative incidence of such events. We have also con- compares with 21% of the NRT trials, and 46% of the bupro- ducted sensitivity analyses, excluding participants known to have pion trials. About 85% of trial outcomes in all three treatments discontinued treatment or to have incomplete data, and found no were biochemically confirmed. Four NRT trials and four bupro- substantive differences in the results. Our approach may nonethe- pion trials were based on conference abstracts only, while all the less be viewed by some as limiting the findings of this overview. varenicline trials used for the meta-analysis were from published reports. Although abstracts are compromised by a lack of detail An intrinsic limitation of conducting an overview is that not every and of peer-review, their inclusion in Cochrane reviews can be component review will be as up to date as we might wish. The justified by the contribution they make to the evidence base. It bupropion review only covers trials available to 2009, and is due has been estimated that more than 50% of trials fail to translate to be updated. We decided against conducting a ’quick and dirty’ to full publication, and that those which do include dispropor- update of the bupropion trials, so as not to compromise the edito-

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 24 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. rial quality of the contributing reviews, but this means accepting each of them with placebo. They also compared bupropion and that the key reviews are not chronologically aligned. varenicline with placebo, and with each other, but did not conduct indirect comparisons between active treatments. They found all treatments to be more effective than placebo, although nico- Agreements and disagreements with other tine inhaler (four trials) did not achieve a statistically significant studies or reviews result compared with placebo. Their direct comparison between varenicline and bupropion detected a lower OR (1.40; 95% CredI Five other systematic overviews of smoking cessation pharma- 0.75 to 2.66; Eisenberg 2008b) than did the other three overviews, cotherapies have been published since the introduction of vareni- which all found a statistically significant effect in favour of varenicline in 2006. Two were restricted to trials in pregnant women cline. The authors commented on this disparity as follows: (Coleman 2012; Myung 2012), with neither identifying any ran- “The wider interval obtained in our analysis ... is a reflection of domised controlled trials of bupropion or varenicline in these pop- how we handled the Nides study, as well as our use of Bayesian ulations. We note them here, but do not discuss them further, techniques, which produce wider intervals than their frequentist other than to observe their findings that the evidence on the sa- equivalents as they incorporate greater uncertainty (particularly fety and efficacy of NRT for smoking cessation in pregnancy is compared with fixed effects models)” (Eisenberg 2013. currently inconclusive. We include the Cochrane Tobacco Addiction Group’s glossary of Our findings are broadly consistent with those of the remaining smoking-related terms Appendix 5. three reviews (Eisenberg 2008a; Mills 2012; Wu 2006). Appendix 4 reports the individual findings from each review. The Mills and Wu reviews were both partially funded by Pfizer Inc (manufacturers of varenicline). The 2006 review by Wu and colleagues, AUTHORS’ CONCLUSIONS although based on fewer trials than our reviews (70 NRT trials versus 122; 12 bupropion trials versus 36; 4 varenicline trials ver- Efficacy for NRT, bupropion and varenicline is well-established sus 15), calculated odds ratios and confidence intervals across all across a strong evidence base. There are fewer trials of cytisine and comparisons similar to those reported in this overview. Outcomes nortriptyline, but current findings indicate that they also improve were biochemically confirmed and assessed at one year or longer. the chances of quitting. The adverse and serious adverse event pro- In the absence of head-to-head data, they conducted indirect com- files are less clearly defined, and rely more heavily upon monitor- parisons between NRT and varenicline, using methods described ing and surveillance systems than on data from trials. in Bucher 1997, which preserve the integrity of the randomisation in individual trials. Mills 2012, with two authors in common with the Wu review, Implications for practice revisits much of the same data. However, the later review stratifies • Both nicotine replacement therapy (NRT) and bupropion outcomes by time of assessment (short-term, three, six and twelve perform similarly compared with placebo in helping people to months), and draws comparisons between standard and high-dose quit (odds ratios (ORs) of 1.84 (95% CredI 1.71 to 1.99) and NRT, and between combination and single NRT formulations, as 1.82 (95% CredI 1.60 to 2.06) respectively). well as direct comparisons between the three different treatments. • Different types of NRT are generally equally effective. They conduct a series of pairwise meta-analyses, and a network meta-analysis using a Bayesian random-effects multiple treatment • Combinations of NRT outperform single formulations comparison. Splitting outcomes by time point produced the oc- (versus patch: OR 1.43 (95% CredI 1.08 to 1.91); versus gum: casional anomalous result, e.g. combination NRT versus placebo/ OR 1.63 (95% CredI1.21 to 2.20); versus ’other’: OR 1.34 control at three months and at one year did not achieve statistically (95% CredI 1.00 to 1.80)). significant effects, and varenicline at six months did not outper- • Varenicline is more effective than NRT or bupropion, when form high-dose nicotine patch, although it was significantly more each is compared with placebo (varenicline vs placebo OR 2.88 effective at all other time points across all other comparisons.Aswe (95% CredI 2.40 to 3.47)). prefer longest follow-up for this overview and for the contributing reviews, we have compared their twelve-month (longest) results • Varenicline is superior to any single type of NRT, and is as with our own outcomes, and found them to be broadly consistent, effective as combinations of NRT (OR 1.06 (95% CredI 0.75 to allowing for their preference for risk ratios rather than odds ratios. 1.48)). Eisenberg 2008a included trials with biochemically validated out- • Varenicline outperforms bupropion in head-to-head comes at six and 12 months, and used the most rigorous definition comparisons (OR 1.59 (95% CredI 1.29 to 1.96)). of abstinence available, i.e. preferring continuous to point prevalence abstinence. They explored NRT efficacy across five different • NRT combined with nortriptyline or with bupropion is not formulations (gum, patch, spray, inhaler and tablet), comparing shown to be more effective than NRT alone.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 25 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. • Cytisine increases the chances of quitting compared with • Further trials of NRT versus placebo are unlikely to modify placebo, without significant adverse or serious adverse events the known benefits and risks of this treatment. (RR 3.98 (95% CI 2.01 to 7.87)) • Nortriptyline approximately doubles the chances of quitting (RR 2.03 (95% CI 1.48 to 2.78)). ACKNOWLEDGEMENTS • Bupropion demonstrates no excess of neuropsychiatric events (RR 0.88 (95% CI 0.31 to 2.50)) or of cardiovascular We thank Paul Aveyard, Linda Bauld and Neal Benowitz for read- events (RR 0.77 (95% CI 0.37 to 1.59)). ing and commenting on the protocol in draft. We thank Edward Mills and Robert Gibbons for reading and commenting on the • Varenicline demonstrates no excess of neuropsychiatric full review in draft, and the Group’s external editorial team (Paul events (RR 0.53 (95% CI 0.17 to 1.67)), and a marginal but Aveyard, John Hughes and Robert West) for advice and comments non-significant increase in cardiovascular events (RR 1.26 (95% at the review stage. We also thank Beverley Shea for discussion CI 0.62 to 2.56)). and advice on revisions to the AMSTAR scale. We thank Monika Epler for interpretation of a Polish trial report. We thank Natalie Implications for research Walker for advice about her ongoing trial of cytisine, and Mark Eisenberg for clarification of data. We thank Robert Gibbons for • Randomised controlled trials comparing varenicline with sight of unpublished data on varenicline’s safety profile. We thank NRT (single and combination formulations) would address Jamie Hartmann-Boyce for assistance with serious adverse events current uncertainties about their respective efficacy and safety. data. • Long-term post-marketing surveillance should continue for The National Institute for Health Research (NIHR) is the largest varenicline, to determine the likelihood of its implication in single funder of the Cochrane Tobacco Addiction Group. The neuropsychiatric and/or cardiac events. views and opinions expressed in the Group’s reviews are those of • Cytisine’s potential as an effective and affordable therapy the authors and do not necessarily reflect those of the NIHR, NHS should be explored through additional large-scale trials. or the Department of Health.

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ADDITIONAL TABLES

Table 1. Characteristics of included reviews

Review ID Assessed as up- Participants Review limita- to-date Interventions Comparisons Outcomes N Pts/trials tions

Antidepres- June 2009 Cur- Bupropion 1. vs placebo 6m+ 1.11440/36 Biochemical sants rent smokers, 2. + NRT vs abstinence: 2. 1106/6 validation was Hughes 2007 mostly NRT alone - all; 3. 657/3 reported in all adult but two 3. vs patch - by setting; 4. 1622/3 B trials except studies of ado- 4. vs vareni- - by level of be- Swan lescents cline havioural sup- 2003, and in port; all N trials ex- - by dosage. cept Da Costa 2002. Nortriptyline 1. vs placebo 6-12m 1. 975/6 Four B 2. +NRT vs 2. 1219/4 trials included NRT alone 3. 417/3 based on ab- 3. vs NRT stracts only. Sensi- Fluoxetine 1. vs placebo 6 or 12m 1. 1236/2 tivity analyses 2. +NRT vs 2. 250/2 of each lim- placebo+NRT itation made no difference Paroxetine vs placebo 6m 224/1 to ﬁndings

Sertraline vs placebo 6m 134/1

MAOIs: 1. vs placebo 12m, 6m 1. 88/1 Moclobemide 2. vs placebo 2. 250/3 Selegiline

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 31 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

Venlafaxine +NRT vs 12m 147/1 placebo+NRT

Anxiolytics October 2009 Any smokers Buspirone 1. vs placebo 1. 12m 409/4 Most trials did Hughes 2011 2. vs NRT 2. 6m not report methods Diazepam vs placebo 6m 76/1 in enough detail to assess Meprobamate 1. vs placebo reduction 216/1 quality of ran- 2. +individual >85% at12m domisation. counselling vs Abstinence of- placebo ten not clearly 3. +group deﬁned or bio- counselling vs validated. placebo Meprobamate outcome was Oxprenolol vs placebo 12m 130/1 reduction, not abstinence. Metoprolol Metoprolol

CB1 receptor January 2011 Adult smokers Rimonabant 1. 20mg vs 50 weeks 1049/2 Study reports antagonists placebo un- (rimonabant) 2. 5mg vs published, not Cahill 2011 placebo peer-reviewed 3. 20mg vs 5mg

Taranabant 1. vs placebo 8 wks N/A N/A

Clonidine June 2008 Adult smokers Clonidine 1. C vs 6m or 12m 776/6 No Gourlay (4/6 placebo details of ran- 2008 trials speciﬁed domisation or heavy blinding; Ab- smokers) stinence not clearly deﬁned

Lobeline January 2009 Any smokers Lobeline 1. vs placebo 6m+ 0/0 N/A Stead 2009 2. vs any treatment

Mecamy- December Healthy vol- Mecamy- 1. +NRT vs 6m or 12m 128/2 Studies lamine 2010 unteer smok- lamine placebo+NRT (no MA) too small to be Lancaster ers 2. +NRT vs conclusive 2011 M vs NRT vs placebo

Nicobrevin January 2009 Adult smokers Nicobrevin 1. vs placebo 6m 0/0 N/A Stead 2009

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 32 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

Nicotine vac- 2012 Adult smok- 1. vs placebo Hatsukami cines ers NicVAX 2. High Ab vs 2011 stratified Hartmann- placebo 12m, 6m 201/1 active group to Boyce 2012 3. 400 vs 200 give the high- - 4 shots est level of sta- - 5 shots tistical signifi- 4. 5 vs 4 shots cance. Nabi - 200ug trials gave in- - 400ug sufficient info to assess

NIC002 12m, 6m 341/1 Possibly post- 1. vs placebo hoc stratiﬁca- 2. High Ab vs tion to give placebo signiﬁcant results

1. Any NRT vs 6m+ 51265/119 In 1.1, 2 tri- placebo 22581/56 als (Shiffman 1. Gum 19586/43 2002, Shiff- 2. Patch 976/4 man 2009) 3. Inhaler 887/4 split into sepa- 4. Nasal spray 3405/7 rate dosage 5. Tabs/ 479/1 comparisons lozenge 2798/5 6. Oral spray 245/1 Adult smokers 7. Choice of 308/1 (not trials that NRT randomised 8. Patch + In- therapists) haler 9. Patch + lozenge October 2012 26% of studies Nico- rated as at low NRT tine Replace- risk of bias for Stead 2013 ment Therapy randomisation, and 5% at high risk. Excluding all but low risk made little difference Variable deﬁnitions of abstinence, including 4 trials

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 33 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

allowing up to 4 cpd; excluding these made no difference 65% reported sustained abstinence, and 80% measured to 12m or more 89% used some form of validation. One third reported some type of blinding. 2. Abstinence -Sus 12m 22581/56 deﬁnition: -Sus 6m 13737/32 1 Gum -PP/ns 12m 4187/8 2 Patch -PP/ns 6m 2501/8 2156/8

19586/43 10928/21 4640/9 2582/6 1436/7

3.Level of sup- Gum or patch: 21759/55 port: - Low -11257/17 1. Gum -High individ- -6891/18 2. Patch ual -3611/20 3. Long vs -High group 19585/43 short: Long vs Short: -4388/12 -Gum -Gum -11559/22 -Patch -Patch -3638/10

800/3 -296/2 -504/1

4. Setting for 6m+ 24199/66 Recruitment/ 8336/28 Treatment: 10816/28 1. Community 443/2 1. Gum 3405/7 2. Patch 412/2 3. Inhaler 308/1

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 34 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

4. Tab/lozenge 479/1 5. Nasal spray 2291/10 6. Combo 1283/6 7. Oral spray 533/2 2. SC Clinic 475/2 1. Gum 11705/23 2. Inhaler 7277/16 3. Nasal spray 4150/6 3. Primary care 278/1 1. Gum 5506/10 2. Patch 2194/3 3. Choice 1042/4 4. Hospitals 245/1 1. Gum 2025/2 2. Patch 1675/4 3. Combo 194/1 4. Choice 1300/2 5. Antenatal 181/1 clinic 5575/5 1. Gum 3297/2 2. Patch 2278/3 3. Choice 6. OTC volun- teers 1. Gum 2. Patch

5. Dosage of 6m+ 856/5 gum 618/4 1. 4mg vs 2mg 238/3 -High dependence -Low dependence

6. Gum: Fixed 6m+ 689/2 vs ad-lib gum

7. 1. Patch: 6m+ 5101/8 High vs stan- 1188/4 dard dosage 467/1 1. 44mg vs 3446/3 22mg 2. 42mg vs 21mg 2. 25mg vs 15mg

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 35 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

8.1. Patch: du- 6m+ /42 ration 7618/11 1. 16hr vs 10820/32 placebo 106/1 2. 24hr vs placebo 3. 24hr vs 16hr

9. 1. Patch: 6m+ /42 Course of treat- 6191/17 ment: 9906/26 1. ≤8 wks /5 2. >8 wks 2861/1 2. Direct com- 568/1 parison 98/1 1. 28 wks vs 12 140/1 wks 80/1 2. 24 wks vs 8 wks 3. 12 wks vs 3 wks 4. 12 wks vs 6 wks 5. 6 wks vs 3 wks

10. 1. Indirect 6m+ 17427/41 comparison 2807/9 1. patch 14620/32 vs placebo; no 264/2 weaning 2. patch vs placebo; with weaning 2. Direct comparison 1. patch; abrupt withdrawal vs weaning

11. 6m+ 4664/9 Combinations: 395/2 1. Long-term 300/1 Smoking cessa- 237/1 tion 1384/1 1. patch+gum 400/1 vs patch alone

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 36 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

2. patch+gum 337/1 vs gum alone 1611/2 3. spray+patch vs patch alone 4. spray+patch vs spray or patch 5. patch+inhaler vs inhaler alone 6. patch+inhaler vs patch or inhaler 7. patch+lozenge vs patch or lozenge

12. 6m+. 3201/6 Direct compar- 222/1 isons between 1272/2 NRTs 1707/3 1. Smoking cessation 1. inhaler vs patch 2. spray vs patch 3. Lozenge vs patch

13. Prescribed 6m+ 820/2 NRT with 300/1 physician sup- 520/1 port vs OTC NRT without support 1.1 patch 1.2 inhaler

14. 1. Precessa- 6m+ 2774/8 tion NRT 1772/6 1. Patch 406/2 2. Gum 596/1 3. Lozenge

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 37 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

15.1 NRT in 1675/4 pregnancy 625/3 1. At end of pregnancy 2. At longest post-partum follow-up.

16. 1. NRT v 6m+ 2544/5 bupropion 1552/4 1. patch vs 781/2 bup 211/1 2. Lozenge vs 1991/3 bup 489/1 3. Choice vs 452/1 bup 526/1 2. Combina- 1991/4 tion vs bupro- 405/1 pion alone 299/1 1. Patch + bup vs bup alone 2. Gum + bup vs bup alone 3. Lozenge + bup vs bup alone 3. Combina- tion vs placebo 1. Patch + bup vs placebo 2. Lozenge+bup vs placebo

17. Palpitations with NRT vs placebo 1. Palpitations/ chest pains

Nicotine re- April 2012 Any adult DianiclineCytisine 2.1. DianiclineCytisine 6m or 12m 602/1937/2 Well-con- ceptor partial smokers (Tabex)1. vs placebo ducted trialtrials agonists 1. vs placebo Cahill 2012 Varenicline 3. Varenicline 6m+ 6166/14 Trials 1mg bid 12+m 378/1 were generally 1. vs placebo 6m 127/1 conducted to a

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 38 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

2. vs placebo high standard, 3. vs placebo with biochem- in pts with i- schizophrenia cally validated outcomes

4. Low-dose 12m 1272/4 varenicline 1083/3 1. V vs placebo 2. Standard V vs low-dose V

5. Varenicline 12m 1622/3 1. vs bupro- 3m 1367/2 pion 6m 1367/2 2. vs bupropion 3. vs bupropion

6. Varenicline 6m 778/2 1. vs NRT (open label)

7. Varenicline 12m 1208/1 as maintenance 6m 1210/1 therapy 1. vs placebo 2. vs placebo at end of double- blind phase

8. Commonest During 3m 6619/16 AEs treatment 6309/15 1. Nausea 5585/12 2. Insomnia 5913/13 3. Abnormal dreams 4. Headache

10. SAEs During 8175/17 1. vs placebo and after treatment

Opioid June 2009 Adult smokers Naltrexone 1. vs placebo 6m or 12m 582/4 Wong antagonists 2. +NRT vs reported data David 2009 placebo+NRT

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 39 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 1. Characteristics of included reviews (Continued)

from only 1 of 4 centres

Silver acetate January 2009 Adult smokers Silver acetate 1. vs placebo 12m 785/2 randomi- Lancaster 2. vs nicotine 414/1 sation not de- 2009 gum scribed. One trial was open- label.

Table 2. AMSTAR scores: NRT, antidepressants and nicotine receptor partial agonists

Question Nicotine Bupropion Nicotine Replacement receptor partial agonists Therapy

1.A priori design provided? CAN’T ANSWER CAN’T ANSWER YES

2. Duplicate study selection and YES YES YES data extraction?

3. Comprehensive literature YES YES YES search performed?

4. Published and unpublished YES YES YES studies included?

5. List of included and excluded YES YES YES studies?

6. Characteristics of included YES YES YES studies provided?

7. Scientiﬁc quality of included YES YES YES studies assessed?

8. Scientiﬁc quality of included YES YES YES studies applied to conclusions?

9. Appropriate methods for YES YES YES combining studies?

10. Likelihood of publication YES NO NO bias?

11. Conﬂict of interest stated? YES YES YES

SCORE 10/11 9/11 10/11

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 40 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 3. AMSTAR scores: other pharmacotherapies

Question Anxiolyt- CB1 re- Clonidine Lobeline Mecamy- Nico- Vaccines Opioid an- Silver ics ceptor an- lamine brevin tagonists acetate tagonists

1.A priori CAN’T YES CANT CAN’T CAN’T CAN’T YES YES CAN’T design pro- ANSWER ANSWER ANSWER ANSWER ANSWER ANSWER vided?

2. Dupli- YES YES YES YES YES YES YES YES YES cate study selection and data extraction?

3. Com- YES YES YES YES YES YES YES YES YES prehensive literature search performed?

4. Pub- YES YES YES YES YES YES YES YES YES lished and unpublished studies included?

5. YES YES YES YES YES YES YES YES YES List of included and excluded studies?

6. Charac- YES YES YES N/A YES N/A YES YES YES teristics of included studies provided?

7. Scien- YES YES YES N/A YES N/A YES YES YES tiﬁc quality of included studies assessed?

8. Scien- YES YES N/A YES N/A YES YES YES tiﬁc quality of included

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 41 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 3. AMSTAR scores: other pharmacotherapies (Continued) studies applied to conclusions?

9. Appro- YES YES YES N/A N/A N/A YES YES YES pri- ate methods for combining studies?

10. Likeli- NO N/A NO N/A YES N/A YES NO N/A hood of publication bias?

11. YES YES YES YES YES YES YES YES YES Conﬂict of interest stated?

SCORE 9/11 10/10 9/11 5/6 9/10 5/6 11/11 10/11 9/10

Table 4. Risk of bias summary for trials in the included reviews

Review N trials randomisation % Sustained Biochemical Blinding % abstinence % validation %

Low Unclear High Low risk risk risk risk

NRT 147 25 72 3 70 86 33

Antidepres- 60 48 50 2 85 85 50 sants

Nic recep par- 24 66 33 - 75 84 58 tial ags

Anxiolytics 7 - 100 - 29 29 0

Clonidine 6 - 100 - 0 67 0

Lobeline 0 No included studies

Mecamy- 2 100 - - 100 100 100 lamine

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 42 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Table 4. Risk of bias summary for trials in the included reviews (Continued)

Nicobrevin 0 No included studies

Nicotine vac- 4 25 75 - 50 50 50 cines

Opioid antag- 4 50 50 - 50 100 100 onists

Rimonabant 3 - 100 - 100 100 0

Silver acetate 2 - 100 - 100 100 50 Numbers from columns 3 to 8 are percentages of the total number of trials for each review.

APPENDICES

Appendix 1. Individual review meta-analyses vs network meta-analyses

Comparison Review OR 95% CI Network OR 95% CI Notes

NRT vs placebo 1.78 1.68 to 1.88 1.84 1.71 to 1.99 119 comparisons

Bupropion vs 1.86 1.66 to 2.08 1.82 1.60 to 2.06 36 comparisons placebo

Varenicline vs 2.83 2.45 to 3.26 2.88 2.40 to 3.47 15 comparisons placebo

Bupropion vs NRT; 1.02 0.84 to 1.24 0.99 0.86 to 1.13 Data from NRT review, 7 trials. Two trials missing from NRT review. Including them drops I² from 41 to 23%, and raises OR from 1.02 to 1.03 (95% CI 0.85 to 1.24)

Varenicline vs 1.66 1.28 to 2.16 1.59 1.29 to 1.96 3 trials (NRT and bupropion reviews agree) bupropion

Varenicline vs NRT N/A N/A 1.57 1.29 to 1.91

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 43 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Appendix 2. Rationale for the choice of priors Our network meta-analyses are based on trial level data, using non-informative priors.The choice of priors remains a contentious issue within any Bayesian framework. It is well recorded that even choosing so-called non-informative priors will have an impact on the findings. However, it is also well understood that this impact reduces as the sample size increases. Results from a recent paper (Thorlund 2013) are entirely consistent with this, where, in the first example, the number of trials included in the model is sparse and the choice of priors has a considerable impact on the estimates (less so in the second example). In our review, the large number of studies included for each one of the head-to-head comparisons makes the choice of priors less crucial in determining the final estimates. As a reflection of this, there is good agreement between the point estimates and the 95% confidence interval and 95% credible interval from the direct and indirect comparisons (Appendix 1).

Appendix 3. Trials, participants and point estimates in the included reviews

DRUG versus TRIALS PTS RR (95% CI)

Bupropion placebo 36 11440 1.69 (1.53 to 1.85)

Bupropion NRT 3 657 1.26 (0.73 to 2.18)

Bupropion + NRT NRT alone 6 1106 1.23 (0.67 to 2.26)

Nortriptyline placebo 6 975 2.03 (1.48 to 2.78)

Nortriptyline + NRT NRT alone 4 1219 1.29 (0.97 to 1.72)

Fluoxetine placebo 2 1236 0.92 (0.65 to 1.30)

Fluoxetine + NRT placebo+NRT 2 250 0.92 (0.53 to 1.61)

Paroxetine placebo 1 224 1.08 (0.64 to 1.82)

Sertraline placebo 1 134 0.71 (0.30 to 1.64)

Moclobemide placebo 1 88 1.57 (0.67 to 3.68)

Selegiline placebo 3 250 1.45 (0.81 to 2.61)

Venlafaxine placebo 1 147 1.22 (0.64 to 2.32)

66 17726

Varenicline placebo 14 6166 2.27 (2.02 to 2.55)

Varenicline low-dose placebo 4 1272 2.09 (1.56 to 2.78)

Varenicline bupropion 3 1622 1.52 (1.22 to 1.88)

Varenicline placebo (maintenance) 1 1208 1.19 (1.03 to 1.36)

Cytisine placebo 2 937 3.98 (2.01 to 7.87)

1 1214 1.61 (1.24 to 2.08)

Dianicline placebo 1 602 1.20 (0.82 to 1.75)

26 13021

NRT placebo 119 51265 1.60 (1.53 to 1.68)

Combination NRT Other forms or mixes of 9 4664 1.34 (1.18 to 1.51) NRT

Physician + NRT OTC NRT 2 820 4.58 (1.18 to 17.88)

Patch before TQD patch from TQD 8 2774 1.18 (0.98 to 1.41)

At end of pregnancy placebo 4 1675 1.30 (1.00 to 1.68)

NRT +/- bupropion bupropion, placebo or 5 2544 1.01 (0.87 to 1.18) patch

147 63742

Rimonabant placebo 2 1049 1.50 (1.10 to 2.05)

2 1049

Buspirone placebo 3 201 0.76 (0.42 to 1.37)

Buspirone NRT patch 1 208 1.08 (0.70 to 1.65)

Diazepam placebo 1 76 1.00 (0.56 to 1.80)

Meprobamate placebo 1 324 0.45 (0.18 to 1.18)

Oxprenolol placebo 1 66 5.31 (0.68 to 41.74)

Metoprolol placebo 1 64 7.52 (1.00 to 56.66)

8 939

Clonidine placebo 6 776 1.63 (1.22 to 2.18)

6 776

Mecamylamine/+-NRT placebo/+-NRT 2 128 No MA data

2 128

Vaccines placebo 2 642 1.35 (0.82 to 2.22)

2 2000 No MA data

4 2642

Naltrexone placebo 2 129 1.34 (0.49 to 3.69)

Naltrexone + NRT placebo + NRT 3 453 1.24 (0.74 to 2.09)

4 582

Silver acetate placebo 2 785 1.04 (0.69 to 1.57)

Silver acetate NRT gum 1 414 0.98 (0.69 to 1.39)

2 1199

TOTALS 267 101,804

Appendix 4. Comparison with other overviews: OR and (95% CI)

NRT vs placebo Bup vs placebo V vs placebo Bup vs NRT NRT vs V OR V vs bup OR

Cahill 2013 1.84 (1.71 to 1. 1.82 (1.6 to 2. 2.88 (2.4 to 3. 0.99 (0.86 - 1. 1.57 (1.29 to 1. 1.59 (1.29 to 1. 99) 122 trials 06) 36 trials 47) 15 trials 13) 91) Indirect 96) 3 trials 9 trials

Wu 2006 1.71 (1.55 to 1. 1.56 (1.10 to 2. 2.96 (2.12 to 4. 1.14 (0.20 to 6. 1.66 (1.17 to 2. 1.58 (1.22 to 2. 88) 70 trials 21) 12 trials 12) 4 trials 42) 2 trials 36) Indirect 05) 3 trials

Mills 2012 1.48 (1.30 to 1. 1.40 (1.22 to 1. 2.39 (1.96 to 2. 0.94 (0.77 to 1. 1.65 1.61 (1.32 to (RRs) 69) 32 trials 60) 27 trials 88) 7 trials 15) Not stated, (1.29 to 2.07) 1 193) not included in trial (Aubin) 3 trials MTC

Eisenberg 2008 1.71 (1.35 to 2. 21) 22 gum trials 2.07 (1.73 to 2. 2.41 (1.91 to 3. 1.40 (0.75 to 2.07 (1.69 to 2. 55) 16 trials 12) 6 trials/13 2.66) 3 trials/5 62) 30 patch tri- groups groups als 2.17 (0.95 to 5. 43) 4 inhaler tri-

als 2.37 (1.12 to 5. 13) 4 spray trials 2.06 (1.12 to 5. 13) 6 tablet trials

Appendix 5. Tobacco Addiction Group Glossary This is a brief topic-specific glossary of terms used in studies of tobacco use and cessation, and in our Group’s reviews. For methodological and statistical terminology used in systematic reviews, see the Glossary of Terms in the Cochrane Collaboration: http:// www3.interscience.wiley.com/homepages/106568753/glossary.pdf Abstinence A period of being quit, i.e. stopping the use of cigarettes or other tobacco products. May be defined in various ways; see also: point prevalence abstinence; prolonged abstinence; continuous/sustained abstinence Biochemical verification Also called ’biochemical validation’ or ’biochemical confirmation’: A procedure for checking a tobacco user’s report that he or she has not smoked or used tobacco. It can be measured by testing levels of nicotine or cotinine or other chemicals in blood, urine, or saliva, or by measuring levels of carbon monoxide (CO) in exhaled breath or in blood. See: SRNT Subcommittee on Biochemical Verificationl ’Biochemical verification of tobacco use and cessation’; Nicotine & Tobacco Research, 2002: 4 (2); 149-59 Bupropion A pharmaceutical drug originally developed as an antidepressant, but now also licensed for smoking cessation; trade names Zyban, Wellbutrin (when prescribed as an antidepressant). Carbon monoxide (CO) A colourless, odourless highly poisonous gas found in tobacco smoke and in the lungs of people who have recently smoked, or (in smaller amounts) in people who have been exposed to tobacco smoke. May be used for biochemical verification of abstinence. Cessation Also called ’quitting’ . The goal of treatment to help people achieve abstinence from smoking or other tobacco use, also used to describe the process of changing the behaviour Continuous abstinence Also called ’sustained abstinence’; cf ’prolonged abstinence’ A measure of cessation often used in clinical trials involving avoidance of all tobacco use since the quit day until the time the assessment is made. The definition occasionally allows for lapses. This is the most rigorous measure of abstinence ’Cold Turkey’ Quitting abruptly, and/or quitting without behavioural or pharmaceutical support Craving A very intense urge or desire [to smoke] See: Shiffman et al ’Recommendations for the assessment of tobacco craving and withdrawal in smoking cessation trials’ Nicotine & Tobacco Research 2004: 6(4): 599-614 Dopamine A neurotransmitter in the brain which regulates mood, attention, pleasure, reward, motivation and movement Efficacy Also called ’treatment effect’ or ’effect size’: The difference in outcome between the experimental and control groups Harm reduction Strategies to reduce harm caused by continued tobacco/nicotine use, such as reducing the number of cigarettes smoked, or switching to different brands or products, e.g. potentially reduced exposure products (PREPs), smokeless tobacco. Lapse/ slip

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 47 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Terms sometimes used for a return to tobacco use after a period of abstinence. A lapse or slip might be defined as a puff or two on a cigarette. This may proceed to relapse, or abstinence may be regained. Some definitions of continuous, sustained or prolonged abstinence require complete abstinence but some allow for a limited number or duration of slips. People who lapse are very likely to relapse, but some treatments may have their effect by helping people recover from a lapse. nAChR [neural nicotinic acetylcholine receptors]: Areas in the brain which are thought to respond to nicotine, forming the basis of nicotine addiction by stimulating the overflow of dopamine Nicotine An alkaloid derived from tobacco, responsible for the psychoactive and addictive effects of smoking. Nicotine Replacement Therapy (NRT) A smoking cessation treatment in which nicotine from tobacco is replaced for a limited period by pharmaceutical nicotine. This reduces the craving and withdrawal experienced during the initial period of abstinence while users are learning to be tobacco-free The nicotine dose can be taken through the skin, using patches, by inhaling a spray, or by mouth using gum or lozenges. Outcome Often used to describe the result being measured in trials that is of relevance to the review. For example smoking cessation is the outcome used in reviews of ways to help smokers quit. The exact outcome in terms of the definition of abstinence and the length of time that has elapsed since the quit attempt was made may vary from trial to trial Pharmacotherapy A treatment using pharmaceutical drugs, e.g. NRT, bupropion, varenicline Point prevalence abstinence (PPA) A measure of cessation based on behaviour at a particular point in time, or during a relatively brief specified period, e.g. 24 hours, 7 days. It may include a mixture of recent and long-term quitters. cf. prolonged abstinence, continuous abstinence Prolonged abstinence A measure of cessation which typically allows a ’grace period’ following the quit date (usually of about two weeks), to allow for slips/ lapses during the first few days when the effect of treatment may still be emerging. See: Hughes et al ’Measures of abstinence in clinical trials: issues and recommendations’; Nicotine & Tobacco Research, 2003: 5 (1); 13-25 Relapse A return to regular smoking after a period of abstinence Second-hand smoke Also called passive smoking or environmental tobacco smoke [ETS] A mixture of smoke exhaled by smokers and smoke released from smouldering cigarettes, cigars, pipes, bidis, etc. The smoke mixture contains gases and particulates, including nicotine, carcinogens and toxins. Self-efficacy The belief that one will be able to change one’s behaviour, e.g. to quit smoking SPC [Summary of Product Characteristics] Advice from the manufacturers of a drug, agreed with the relevant licensing authority, to enable health professionals to prescribe and use the treatment safely and effectively. Tapering A gradual decrease in dose at the end of treatment, as an alternative to abruptly stopping treatment Tar The toxic chemicals found in cigarettes. In solid form, it is the brown, tacky residue visible in a cigarette filter and deposited in the lungs of smokers. Titration A technique of dosing at low levels at the beginning of treatment, and gradually increasing to full dose over a few days, to allow the body to get used to the drug. It is designed to limit side effects. Withdrawal A variety of behavioural, affective, cognitive and physiological symptoms, usually transient, which occur after use of an addictive drug is reduced or stopped. See: Shiffman et al ’Recommendations for the assessment of tobacco craving and withdrawal in smoking cessation trials’ Nicotine & Tobacco Research 2004: 6(4): 599-614

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 48 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. WHAT’S NEW Last assessed as up-to-date: 16 November 2012.

Date Event Description

7 July 2015 Amended Citation of Mills 2010 corrected

CONTRIBUTIONSOFAUTHORS KC and TL developed the concept of this overview. RP was responsible for the statistical approach and the methodology, and SS conducted the network meta-analyses. KC conducted the search and wrote the review, and all authors contributed to the ﬁnal version.

DECLARATIONSOFINTEREST Three authors of this overview (KC, RP, TL) have contributed to many of the included reviews.

SOURCES OF SUPPORT

Internal sources • Department of Primary Care Health Sciences, University of Oxford, UK. • National School for Health Research School for Primary Care Research, UK.

External sources • National Institute for Health Research (NIHR), UK.

INDEX TERMS

Medical Subject Headings (MeSH) ∗Tobacco Use Cessation Products; Alkaloids [therapeutic use]; Antidepressive Agents, Second-Generation [∗therapeutic use]; Azocines [therapeutic use]; Benzazepines [∗therapeutic use]; Bupropion [∗therapeutic use]; Nicotinic Agonists [∗therapeutic use]; Nortriptyline [therapeutic use]; Quinolizines [therapeutic use]; Quinoxalines [∗therapeutic use]; Randomized Controlled Trials as Topic; Review Literature as Topic; Smoking [drug therapy]; Smoking Cessation [∗methods]; Varenicline

Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 49 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. MeSH check words Adult; Humans